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Stevens-Johnson syndrome: knowing the signs and symptoms

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 CLINICAL REVIEW
Stevens-Johnson syndrome:
knowing the signs and symptoms
While most adverse cutaneous drug eruptions are benign, healthcare professionals should
be alert to specific red flags for rare but potentially fatal disorders such as SJS and TENS
Case scenario
A 30-YEAR-OLD MAN was admitted to the acute psychi-
atric unit following a first acute manic episode. He was
commenced on olanzapine and during admission, carba-
mazepine was added as an adjunct treatment. Following
his discharge, he developed an acute painful full-body
rash with blisters on his palms and oral mucosa after two
weeks of commencement of carbamazepine.
He was referred to the emergency department by his
general practitioner and was discharged the same day.
His GP reviewed him the following day and a diagnosis
of Stevens-Johnson syndrome was made. His GP discon-
tinued carbamazepine and he was promptly readmitted to
the hospital for observation. The rash gradually resolved,
and the desquamation of his palm recovered after six
weeks.
STEVENS-JOHNSON SYNDROME (SJS) is a rare
cutaneous disorder that can develop acutely but is often
overlooked. It presents on the less severe end of the SJS/
TEN (toxic epidermal necrolysis) spectrum of disease. SJS
is a rare but potentially fatal disorder of the skin and mucous
membranes. Initial presentation may include flu-like symp-
toms, fever or chills, which may lead to the manifestation
of a rash, blisters, burning sensation and sores. SJS has a
mortality rate of 16-30%,1 which increases after the first
year if left untreated. Although often linked to toxic epider-
mal necrolysis, two major differentiating factors between
SJS and TEN are the more severe skin detachment seen in
TEN, as well as the fact that SJS covers < 10% of the skin,
with TEN covering > 30%.2
Around 90% of patients with SJS will present with
mucosal lesions.3 These lesions typically originate on the
face and thorax and then spread across the body. Lesions
can affect various bodily systems such as the genitouri-
nary tract, mouth and eyes. Most recorded cases of SJS
have been due to a hypersensitivity reaction secondary
to medication, however, autoimmune diseases and some
infections have also been linked to SJS.3
Treatment usually consists of stopping the precipitating
medication and administering IV fluids, antibiotics, and
analgesics; in severe cases, surgical treatment (skin graft-
ing) may be needed.
SJS is predominantly triggered by medication, thus
making it difficult to prevent. Once a medication or its
metabolite is identified as precipitation for SJS, that agent
should be avoided in order to prevent further adverse
reactions.
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HOSPITAL DOCTOR OF IRELAND
Pathogenesis
Stevens-Johnson syndrome is a type IV hypersensitiv-
ity reaction, which is a delayed response reaction. Unlike
others, it is a cell-mediated response as opposed to an
antibody-mediated response. It is believed the reaction
against the trigger factor causes an increased produc-
tion of CD8 or CD4 T cells and cytokines, which induce
apoptosis of the keratinocytes, hence initiating the auto-
immune reaction within the body.4 The overreaction of
the cytokines and helper T cells eventually causes inflam-
mation, tissue damage and ultimately cell death. The type
IV hypersensitivity reaction can usually be resolved with
topical corticosteroids and avoidance of the trigger.
The drug or the metabolites subvert the antigen pres-
entation pathways of the innate immune system within
the body. The drug or metabolite then binds with a host
protein to form a non-self epitope (foreign material); this
is then taken up by an antigen-presenting cell (APC) and
digested into small peptides.4 The peptides are placed
on the HLA component of the major histocompatibility
complex (MHC) and are presented to the body’s T cell
receptors. Once the non-self epitopes are bound to a T cell
receptor, it stimulates the receptor-bearing parent T cell to
initiate attacks on the body’s tissues. A second mechanism
for the sensitivity reaction is that the non-self epitope
inserts itself into the groove on the HLA protein.5
The third theory is that the non-self epitope binds out-
side the groove to alter a HLA protein. This is done by
binding to a specific HLA serotype and producing T cells.6
Due to the fact that only 13,000 HLA serotypes exist, and
any individual would express only a few, severe cutane-
ous adverse reactions (SCARs) to an SJS-inducing drug
or its metabolite is a rare occurrence.6 As a result of this,
it stands that some specific genetic groups and ethnici-
ties are predisposed to type IV hypersensitivity reactions
to SJS-inducing drugs or its metabolite. HLA-B*1502
(HLA-B75) serotype7 is associated with Han Chinese and
Thai populations. Similar to the East Asian population,
HLA-B*5801 (HLA-B58)8 serotype was also found in
around 3% of the European population.9
Causes of Stevens-Johnson syndrome
A multitude of factors can cause Stevens-Johnson syn-
drome, however, it can also occur without a known cause.
The most common cause of SJS is medication. It can usu-
ally take one to three weeks following the commencement
of the drug for symptoms to appear.2 The most common
groups of medications known to trigger SJS are:
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 CLINICAL REVIEW HOSPITAL DOCTOR OF IRELAND

Table 1. Erythema multiforme major (EMM) versus SJS/TEN14

EMM SJS/TEN
Hallmark lesion Raised, papular typical target lesions: dusky Flat, macular with ill-defined borders
oedematous area surrounded by a darker, that may progress to vesicles and bullae
erythematous inflammatory zone further followed by skin sloughing. Tender to
surrounded by a lighter oedematous ring, palpation and diffusely erythematous.
enclosed by an erythematous zone +/- Typical target lesions
atypical targetoid lesions
Distribution of lesions Face and extremities/acral Face and trunk
Constitutional symptoms Uncommon Common
Mucosal involvement 25-60% > 87%
Ocular involvement Uncommon Common

Urethritis Uncommon Common

Blister formation Uncommon Common

Typical age 20-40 years Elderly

Gender Males > females Females > males

Precipitating factors 1. Infectious (most commonly HSV-1)* Drugs: NSAIDS, sulfonamides,

Duration of symptoms
2. Drugs (NSAIDS, sulfonamides,
antiepileptics and antibiotics)
3. Exposures (poison ivy)
4. Systemic disease (inflammatory bowel
disease, Behcet disease)
5. Idiopathic
1-2 weeks
antiepileptics, antibiotics (especially
penicillins), antimalarials and HAART
Less commonly: infectious*
8-12 days acute phase, re-epitheliasation
takes 2-4 weeks

Association with No Yes

cancer, HIV, HLA type
or collagen vascular
disease
*Other infectious etiologies include: Cyomegalovirus, Coxsackievirus, Parvovirus B19, Histoplasma capsulatum and
Dermatophytes

• Anti-epileptic drugs (phenytoin, carbamezapine, lamo- • Varicella zoster virus

trigine phenobarbital and valproate) • Epstein-Barr virus
• Antibiotics (aminopenicillins, cephalosporins and • Salmonella
fluoroquinolones) • Adenovirus
• Antiretroviral drugs (nevirapine) • Hepatitis virus
• Antibacterial sulfa drugs (sulfasalazine, cotrimoxa- • Mycobacterium tuberculosis
zole) • Chlamydia psittaci.2
• NSAIDs (diclofenac, meloxicam, piroxicam).
• Other miscellaneous drugs (allopurinol, chlormezanone).2 Risk factors for developing SJS
Although less likely, vaccinations such as the influ- Factors that contribute to a greater risk of develop-
enza vaccine,3 smallpox vaccine10 and MMR vaccines,11 ing SJS are those which effectively weaken the immune
as well as graft-versus-host disease, can also be a trig- system. These include HIV, SLE, cancer and a history of a
ger for SJS. They achieve this by stimulating a delayed bone marrow transplant. Other significant risk factors are
hypersensitivity reaction within a usually compromised having a positive family history of SJS and having one of
immune system. the specific variations of the HLA-B gene, as discussed
Infections can also cause SJS, including: above.12
• Mycoplasma pneumonia (the most common cause in
children) Symptoms of SJS
• HIV Careful clinical/medical history taking from a patient

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 CLINICAL REVIEW HOSPITAL DOCTOR OF IRELAND

Table 2. Severity-of-Illness Score for toxic epidermal necrolysis (SCORTEN)17

Risk factor* Score (0) Score (1)
Age < 40 years ≥ 40 years
Associated cancer No Yes
Heart rate (beats/minute) < 120 ≥ 120
Serum blood urea nitrogen ≤ 28mg/dL (10mmol/L) > 28mg/dL (10mmol/L)
Detached or compromised body surface < 10% ≥ 10%
Serum bicarbonate ≥ 20mEq/L (≥ 20mmol/L) < 20mEq/L (< 20mmol/L)
Serum glucose ≤ 250mg/dL (≤ 13.88mmol/L) > 250mg/dL (> 13.88mmol/L)
* More risk factors indicate a higher score and a higher mortality rate (%) as follows:
• 0-1 = 3.2% (CI: 0.1 to 16.7) • 2 = 12.1% (CI: 5.4 to 22.5)
• 3 = 35.3% (CI: 19.8 to 53.5) • 4 = 58.3% (CI: 36.6 to 77.9)
• ≥ 5 = > 90% (CI: 55.5 to 99.8) CI = confidence interval

suspected of SJS is monumental to diagnosis. Recogni- Diagnosis

tion of the symptoms of SJS is crucial and potentially
lifesaving. These primarily include dermatological
manifestations but can also involve other systems. Flu-
like symptoms such as fever, cough and body aches can
develop initially, followed by skin pain, flat red rash/
blotches on the skin, and mucous membranes such as
eyes, mouth, throat, genitals and anus, which result in
the peeling of the skin. The patient may also experience
painful micturition and sealing of the eyes (secondary to
blistering of mucous membrane and swelling) and drool-
ing (if difficulty in closing mouth).3
Differential diagnosis
Stevens-Johnson syndrome primarily affects the
dermis, and many other conditions may present similarly
to SJS, the predominant one being TEN. The appearance
of the lesions, the progression of symptoms and taking
a skin biopsy are key tools to differentiate between SJS
and other conditions. One of the most important ways to
distinguish between the two is that SJS covers < 10% of
the body surface, whereas TEN affects > 30%. A positive
Nikolsky sign (skin sloughing at pressure points show-
ing nephrotic epithelium on histological examination)
is indicative of severe TEN.2 In the later stages of SJS/
TEN, differential diagnosis also includes toxic shock
syndrome (more prominent organ involvement and dif-
ferent cutaneous manifestations such as macular rash on
palms and soles), exfoliative erythroderma (usually spar-
ring mucous membranes) and erythema multiforme major
(with mucous involvement). Differentiating criteria are
shown in Table 1; other severe cutaneous adverse reac-
tions (SCARs), such as drug reaction with eosinophilia
and systemic symptoms (DRESS) syndrome and rarely
acute generalised exanthematous pustulosis (AGEP), are
included.13
In children, SJS must be distinguished from staphylo-
coccal scalded skin syndrome (SSSS) – clinical suspicion
of staphylococcal infection, absence of medication his-
tory and no effect on mucous membranes.
Due to the myriad of differential diagnoses with non-
specific dermatological manifestations, an essential tool
in the diagnosis of SJS is an in-depth history of the devel-
opment, duration, level of associated pain and a full past/
present medication history.
The usual progression of SJS begins with prodromal
symptoms that resemble flu or upper respiratory tract
infection (URTI), and may last several days. This is fol-
lowed by a sudden onset of a painful red skin rash initially
presenting on the trunk and quickly spreading to the face
and limbs over days to weeks (rarely affecting soles, scalp
or palms). The maximum extent of the rash is usually
completed by four to 30 days.1
On physical examination, it is crucial to assess the skin
and mucous membranes (usually at least two mucous
membranes are affected, eg. eyes, mouth, oesophagus,
genitals) and the body percentage of the affected skin
(< 10%). The lesions may be macules (flat, red) diffuse
erythema, blisters (flaccid), and, in severe cases of TEN,
the blisters merge and produce sheets of skin detachment
that expose weepy dermis. A skin biopsy is the gold stand-
ard of investigations that can be carried out to diagnose
SJS.15
Treatment of SJS
The most significant determinant in treating SJS is
establishing the underlying cause, usually evident through
clinical history taking. If the cause is medication, then that
medication needs to be safely stopped. Other treatments
depend on the severity of symptoms. The severity also
determines whether patients are treated in outpatient set-
tings or require hospitalisation with referral to specialised
units (ICU or a burns unit). Other treatments may include
analgesics, antibiotics (can be used prophylactically),
replacing electrolytes (IV fluids), and non-adhesive
dressings on affected areas. Input from specialised teams
(dermatology and ophthalmology) to perform skin
grafts and amniotic membrane grafts should be utilised
if needed. In more severe cases of SJS, patients may be
treated with IV immunoglobulin, IV cyclosporine and

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 CLINICAL REVIEW
IV steroids. The promotion of healing using high-calorie
foods (possibly by tube feeding) has also been proven to
benefit patients.16
Prognosis and complications
The prognosis of SJS is non-uniform and differs
between individuals. In some cases, it takes only a
few weeks for the skin to regenerate, whereas in other
patients, the effects of SJS can take months to recover
fully. The SCORTEN (Severity-of-Illness Score for Toxic
Epidermal Necrolysis) in Table 2 can be used to assess the
severity and prognosis of TEN.
The mortality rate of SJS is 16-30% as it is on the less
severe end of the SJS/TEN spectrum.1 The complications
include:
• Dehydration and acute malnutrition
• Skin – itching, change in colour, dryness, excessive
sweating
• Pulmonary – pneumonia, acute respiratory distress
syndrome
• Alopecia
• Nail damage, nail loss
• Eyes – photophobia, disturbances in vision, chronic
swelling/dryness/irritation
• Changes in taste
• Dryness of mucous membranes (can affect urination
in some cases)
• Chronic fatigue syndrome
• Gastrointestinal ulceration
• Disseminated intravascular coagulopathy
• Multiple organ failure
• Shock
• Septicaemia.18
It is possible to experience a relapse of SJS if a patient
is exposed to the same medication or other known trig-
gers involved in the initial development of the condition.
In these cases, it is common for the second episode to be
more severe than the first, therefore negatively impacting
the overall prognosis of the illness.18
Conclusion
Stevens-Johnson syndrome and toxic epidermal
necrolysis (TEN) are severe cutaneous hypersensitivity
reactions. They are on the same spectrum, with SJS being
on the less severe end. Drugs, in particular anti-epileptics,
sulfa-drugs and antibiotics, are among the most common
causes, with others being infection, graft-versus-host
disease and vaccines. In SJS, diagnosis is usually made
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HOSPITAL DOCTOR OF IRELAND
evident by the appearance of the initial lesions and clini-
cal history taking. Treatment usually consists of stopping
the causative agent, replenishing electrolyte imbalance
and treating the lesions with dressings. In severe SJS/TEN
IV cyclosporine cases, IV immunoglobulin therapy, skin
grafts and treatments in specialised ICU/burns units may
be necessary. With dermatological manifestations, a high
clinical suspicion should be held for SJS and TEN as their
mortality rates are 10% and 30%, respectively.
References
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my.clevelandclinic.org/health/diseases/17656-stevens-johnson-syndrome
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carbamazepine-induced Stevens–Johnson Syndrome. Drug Saf Case Rep
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Johnson Syndrome/toxic epidermal necrolysis: subtle difference in
presentation, major difference in management. Military Med 2020; 185(9-
10):e1847-50
15. Lin Y, Sheu J, Chung W et al. Vancomycin-induced Stevens-Johnson
Syndrome in a boy under two years old: An early diagnosis by Granulysin
Rapid Test. Front Pediatr 2018; 6:26
16. Kirchhof M, Miliszewski M, Sikora S, Papp A, Dutz J. Retrospective review
of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment
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Dermatol 2014; 71(5):941-7
17. Fouchard N, Bertocchi M, Roujeau J, Revuz J, Wolkenstein P, Bastuji-Garin
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J Invest Dermatol 2000; 115(2):149-53
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toxic-epidermal-necrolysis
Dr Hanardi Suliman, Senior House Officer, Dr Stelios
Naxakis, Senior Registrar, and Dr Muhammed Fahmi
Ismail, Consultant Psychiatrist, University Hospital
Kerry
Dec 2021 / Jan 2022; Vol 27 No 10 00