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Stevens-Johnson syndrome: knowing the signs and symptoms

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 CLINICAL REVIEW HOSPITAL DOCTOR OF IRELAND

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 Pathogenesis

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

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

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 CLINICAL REVIEW HOSPITAL DOCTOR OF IRELAND

IV steroids. The promotion of healing using high-calorie evident by the appearance of the initial lesions and clini-
foods (possibly by tube feeding) has also been proven to cal history taking. Treatment usually consists of stopping
benefit patients.16 the causative agent, replenishing electrolyte imbalance
and treating the lesions with dressings. In severe SJS/TEN
Prognosis and complications IV cyclosporine cases, IV immunoglobulin therapy, skin
The prognosis of SJS is non-uniform and differs grafts and treatments in specialised ICU/burns units may
between individuals. In some cases, it takes only a be necessary. With dermatological manifestations, a high
few weeks for the skin to regenerate, whereas in other clinical suspicion should be held for SJS and TEN as their
patients, the effects of SJS can take months to recover mortality rates are 10% and 30%, respectively.
fully. The SCORTEN (Severity-of-Illness Score for Toxic References
Epidermal Necrolysis) in Table 2 can be used to assess the 1. Diphoorn J, Cazzaniga S, Gamba C et al. Incidence, causative factors
and mortality rates of Stevens-Johnson syndrome (SJS) and toxic
severity and prognosis of TEN. epidermal necrolysis (TEN) in northern Italy: data from the REACT registry.
Pharmacoepidemiol Drug Saf 2015; 25(2):196-203
The mortality rate of SJS is 16-30% as it is on the less 2. Benedetti J. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal
severe end of the SJS/TEN spectrum.1 The complications Necrolysis (TEN) - Dermatologic Disorders - MSD Manual Professional
Edition [Internet]. MSD Manual Professional Edition. 2021 [cited 15 August
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3. Harr T, French L. Toxic epidermal necrolysis and Stevens-Johnson
syndrome. Orphanet J Rare Dis 2010; 5(1)
sweating 4. Hoetzenecker W, Nägeli M, Mehra E et al. Adverse cutaneous drug
eruptions: current understanding. Semin Immnopath 2015; 38(1):75-86
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Dermatol 2018; 178(3):614-8
syndrome 6. Duong T, Valeyrie-Allanore L, Wolkenstein P, Chosidow O. Severe cutaneous
• Alopecia adverse reactions to drugs. Lancet 2017; 390(10106):1996-2011
7. Locharernkul C, Loplumlert J, Limotai C et al. Carbamazepine and
• Nail damage, nail loss phenytoin induced Stevens-Johnson syndrome is associated with HLA-
B*1502 allele in Thai population. Epilepsia 2008; 49(12):2087-91
• Eyes – photophobia, disturbances in vision, chronic 8. Alfirevic A, Jorgensen A, Williamson P et al. HLA-B locus in Caucasian
swelling/dryness/irritation
patients with carbamazepine hypersensitivity. Pharmacogenomics 2006;
7(6):813-8
• Changes in taste 9. Lonjou C, Borot N, Sekula P et al. A European study of HLA-B in Stevens–
Johnson syndrome and toxic epidermal necrolysis related to five high-risk
• Dryness of mucous membranes (can affect urination drugs. Pharmacogenet Genomics 2008;18(2):99-107
10. Shetty S, Chatra L, Shenai P, Rao P. Stevens-Johnson syndrome: a case
in some cases) report. J Oral Sci 2010; 52(2):343-6
• Chronic fatigue syndrome 11. Oluwo A, Irewole-Ojo F, Mabogunje C. Oral manifestations of herbal
medicine induced Steven Johnson syndrome in three Nigerian paediatric
• Gastrointestinal ulceration patients: case report. PAMJ Clin Med 2020; 4(92)
12. Steven-Johnson Syndrome (SJS): Causes, rash & Treatments [Internet].
• Disseminated intravascular coagulopathy Cleveland Clinic 2021 [cited 4 August 2021]. Available from: https://
• Multiple organ failure
my.clevelandclinic.org/health/diseases/17656-stevens-johnson-syndrome
13. Masuka J, Muzopambwa G, Khoza S, Chibanda D. An interesting case of
• Shock carbamazepine-induced Stevens–Johnson Syndrome. Drug Saf Case Rep
2019; 6(1):1
• Septicaemia.18 14. Newkirk R, Fomin D, Braden M. Erythema Multiforme versus Stevens–
Johnson Syndrome/toxic epidermal necrolysis: subtle difference in
It is possible to experience a relapse of SJS if a patient presentation, major difference in management. Military Med 2020; 185(9-
is exposed to the same medication or other known trig- 10):e1847-50
15. Lin Y, Sheu J, Chung W et al. Vancomycin-induced Stevens-Johnson
gers involved in the initial development of the condition. Syndrome in a boy under two years old: An early diagnosis by Granulysin
Rapid Test. Front Pediatr 2018; 6:26
In these cases, it is common for the second episode to be 16. Kirchhof M, Miliszewski M, Sikora S, Papp A, Dutz J. Retrospective review
more severe than the first, therefore negatively impacting
of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment
comparing intravenous immunoglobulin with cyclosporine. J Am Acad
the overall prognosis of the illness.18 Dermatol 2014; 71(5):941-7
17. Fouchard N, Bertocchi M, Roujeau J, Revuz J, Wolkenstein P, Bastuji-Garin
S. SCORTEN: A Severity-of-Illness Score for Toxic Epidermal Necrolysis.
J Invest Dermatol 2000; 115(2):149-53
Conclusion 18. Ngan V. Stevens Johnson Syndrome/Toxic Epidermal Necrolysis. SJS/
Stevens-Johnson syndrome and toxic epidermal TEN | DermNet NZ [Internet]. Dermnetnz.org. 2021 [cited 14 August 2021].
Available from: https://dermnetnz.org/topics/stevens-johnson-syndrome-
necrolysis (TEN) are severe cutaneous hypersensitivity toxic-epidermal-necrolysis

reactions. They are on the same spectrum, with SJS being

on the less severe end. Drugs, in particular anti-epileptics, Dr Hanardi Suliman, Senior House Officer, Dr Stelios
sulfa-drugs and antibiotics, are among the most common Naxakis, Senior Registrar, and Dr Muhammed Fahmi
causes, with others being infection, graft-versus-host Ismail, Consultant Psychiatrist, University Hospital
disease and vaccines. In SJS, diagnosis is usually made Kerry

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