International Journal of Pharmacological Research www.ssjournals.

com
ISSN: 2277-3312 Journal DOI:10.7439/ijpr

Steven Johnson syndrome and toxic epidermal necrolysis: A review

Sriram Anne*, Sreya Kosanam, and Lakshmi Prasanthi N

Hindu college of Pharmacy, Amaravathi Road, Guntur-522006, India.

Corresponding author*
Sriram Anne,
Hindu College of Pharmacy,
Amaravathi Road, Guntur-522006, India.
E-mail: anne.sriram@gmail.com

Abstract
Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug
reactions that involve the skin and mucous membranes. They are characterized by mucocutaneous tenderness and
hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting in areas of total skin. Drugs
are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex
virus infections are well documented causes rare cases in which the etiology remains unknown. Several drugs are at
"high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-
antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID.
Differential diagnosis includes IgA-dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous
pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and
staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN
requires rapid diagnosis, identification and interruption of the drugs, specialized supportive care ideally in an intensive
care unit, and provision of immunomodulating agents such as high-dose intravenous immunoglobulin therapy.

Keywords: Toxic epidermal necrolysis, Stevens Johnson Syndrome, skin and mucous membranes.

1. Introduction
Stevens-Johnson syndrome (SJS) is an immune-complexmediated hypersensitivity complex that typically
1
involves the skin and the mucous membranes . Stevens-Johnson syndrome was first described in 1922 as an extraordinary
and generalized epidermal eruption. It is accompanied by fever, inflammation of the buccal mucosa, and severe purulent
conjunctivitis. Incidence of this disorder is unknown, but it is thought to be very low. The etiology of this disorder is
multiple, including drugs, infectious agents, and idiopathic causes. The mortality rate mainly depends on the age and health
of the patient, and rates can range from 30 to 100 percent. Individuals with the very young or the old, are usually fatal
2-5
cases. Death is commonly due to infectious complications .
6,7
Toxic epidermal necrolysis (TEN) is usually drug-reaction . Drugs are an important cause of StevensJohnson
syndrome, but infections or a combination of infections and drugs has also been implicated. In case reports and studies,
8-13
more than 100 drugs have been implicated as causes of StevensJohnson syndrome or toxic epidermal necrolysis . A
limited number of drugs, including sulfonamides, anticonvulsant agents, and allopurinol, are the most consistently
associated with the conditions; whether nonsteroidal anti-inflammatory drugs (NSAIDs), analgesic agents, and
nonsulfonamide antibiotics are associated with them is controversial. The relative risk associated with the use of specific
drugs has never been quantified.
1
The simplest classification breaks the disease down as follows :
Stevens-Johnson syndrome: A minor form of toxic epidermal necrolysis, with less than 10% body surface area
(BSA) detachment
Overlapping Stevens-Johnson syndrome/toxic epidermal necrolysis: Detachment of 10-30% of the BSA.
Toxic epidermal necrolysis: Detachment of more than 30% of the BSA.

Both SJS and TEN are debatably included in the same spectrum as Erythema Multiforme (EM). This mucocutaneous
11,14
condition has similarities in clinical presentation to SJS/TEN but has some distinct differences as mentioned in table-1
and figure-1.

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Table-1: Similarities in clinical presentation
Characteristics EM SJS SJS-TEN overlap TEN
%BSA involved in detachment <10% <10% 10-30% >30%
1 mucous membrane affected Up to 70% >90% >90% >90%
Spots No Yes Yes Yes
Atypical targets Raised Flat Flat Flat
Mortality Rare 10% 30% 50%
Common cause Infection Medication Medication Medication
Recurrent Yes (30%) No No No
Sequelae Rare Common Common Common

Figure: 1: Difference in severity of disease

2. Etiology
Various etiologic factors have been implicated as causes of Stevens-Johnson syndrome. Drugs most commonly
are blamed. The 4 etiologic categories are as follows:
Infectious
Drug-induced
Malignancy-related
Idiopathic
2.1. Infectious causes
Viral diseases that have been reported to cause Stevens-Johnson syndrome include the following:
Herpes simplex virus (possibly; remains a debated issue)
AIDS
Coxsackie viral infections
Influenza
Hepatitis
Mumps
In children, Epstein-Barr virus and enteroviruses have been identified. More than half of the patients with
Stevens-Johnson syndrome report a recent upper respiratory tract infection.
Bacterial etiologies include the following:

Group A beta-hemolytic streptococci

Diphtheria

Brucellosis

Lymphogranuloma venereum

Mycobacteria
15,16
Mycoplasma pneumonia

Rickettsial infections

Tularemia

Typhoid
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2.2. Drug induced

Antibiotics are the most common cause of Stevens-Johnson syndrome, followed by analgesics, cough and cold
medication, NSAIDs, psychoepileptics, and antigout drugs. Of antibiotics, penicillins and sulfa drugs are prominent;
17
ciprofloxacin has also been reported .
The following anticonvulsants have been implicated:
Phenytoin
Carbamazepine
oxcarbazepine (Trileptal)
Valproic acid
Lamotrigine
Barbiturates
18
Belong to Mockenhapupt et al that most anticonvulsant-induced SJS occurs in the first 60 days of use .
19
Antiretroviral drugs implicated in Stevens-Johnson syndrome include nevirapine and possibly other non-nucleoside.
Stevens-Johnson syndrome has also been reported in patients taking the following drugs:

Modafinil (Provigil)
20
Allopurinol
21
Mirtazapine
22
TNF-alpha antagonists (eg, infliximab, etanercept, adalimumab)

Cocaine

Sertraline

Pantoprazole

Tramadol
2.3. Genetic factors:
Carriage of the following human leukocyte antigens has been associated with increased risk:
HLA-B*1502
HLA-B*5801
HLA-B*44
HLA-A29
HLA-B12
HLA-DR7
HLA-A2
HLA-B*5801
HLA-A*0206
HLA-DQB1*0601
Certain of these HLA alleles are associated with an increased probability of developing Stevens-Johnson
23
syndrome upon exposure to specific drugs. HLA-B*5801 confers a risk of allopurinol-related reactions. Pretreatment
24
screening is not readily available. HLA-A29, HLA-B12, and HLA-DR7 are frequently associated with sulfonamide-
induced Stevens-Johnson syndrome, while HLA-A2 and HLA-B12 are often encountered in Stevens-Johnson syndrome
induced by nonsteroidal anti-inflammatory drugs (NSAIDs). HLA-A*0206 and HLA-DQB1*0601 allele have been shown
25,26
to be was strongly associated with Stevens-Johnson syndrome with ocular disease. Nevertheless, whether the presence
of those genes constitutes a predisposition to Stevens-Johnson syndrome or whether those genes are in linkage
27
disequilibrium with more relevant adjacent genes is unknown.

3. Signs and symptoms

Typical prodromal symptoms during two weeks of Stevens-Johnson syndrome are as follows:
Cough productive of a thick, purulent sputum
Headache
Malaise
Arthralgia
Patients may complain of a burning rash that begins symmetrically on the face and the upper part of the torso. The
cutaneous lesions are characterized as follows:
The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or erythema
In contrast to the typical lesions of erythema multiforme, these lesions have only 2 zones of color
The lesions core may be vesicular, purpuric, or necrotic; that zone is surrounded by macular erythema
Lesions may become bullous and later rupture, leaving denuded skin; the skin becomes susceptible to secondary
infection
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Sriram Anne Review Article
Urticarial lesions typically are not pruritic
Infection may be responsible for the scarring associated with morbidity
Although lesions may occur anywhere, the palms, soles, dorsum of the hands, and extensor surfaces are most
commonly affected
The rash may be confined to any one area of the body, most often the trunk
Signs of mucosal involvement can include the following:
Erythema
Edema
Ulceration
Necrosis
The following ocular signs may be noted on slit-lamp examination:
Eyelids: Trichiasis, distichiasis, meibomian gland dysfunction, blepharitis
Conjunctiva: Papillae, follicles, keratinization, subepithelial fibrosis, conjunctival shrinkage, foreshortening of
fornices, symblepharon, ankyloblepharon
Cornea: Superficial punctate keratitis, epithelial defect, stromal ulcer, neovascularization, keratinization, limbitis,
conjunctivalization, stromal opacity, perforation.

4. Pathophysiology
The pathogenesis of SJS/TEN is not entirely based on the immune reaction, but also trusted with a implicating of
29,29
hypersensitivity reaction type III and IV .
Patients who are immunocompromised (especially those infected with HIV 30,31 ), and patients with brain tumors
has slow acetylators whose liver cannot completely detoxify reactive drug metabolites. These drug metabolites may have
32,33
direct toxic effects or may act as haptens that interact with host tissues, rendering them antigenic.
Both SJS and TEN are characterised by the detachment of epidermis from the papillary dermis at the epidermal-
36,37
dermal junction, manifesting as a papulomacular rash and bullae as a result of keratinocyte apoptosis . Keratinocyte
apoptosis mediated by cytotoxic T-lymphocytes (CD8) in SJS and TENS is modulated by plasma TNF-alpha and
38,39
interferon-gamma, which are increased in patients with SJS and TEN .

5. Diagnosis
The diagnosis relies on the one hand on clinical symptoms and on the other hand on histological features. Typical
clinical signs initially include areas of erythematous and macules on the skin, on which a positive Nikolsky sign can be
induced by mechanical pressure on the skin, followed within minutes to hours by the onset of epidermal detachment
characterized. To distinguish SJS, SJS-TEN and TEN the surface area of the detachment is the main discriminating factor.
Histological work up of immediate cryosections or conventional formalin-fixed sections of the skin revealing wide spread
necrotic epidermis involving all layers confirms the diagnosis.
5.1. Differential diagnosis
Major differential diagnosis of SJS/TEN are autoimmune diseases, including IgA-dermatosis and paraneoplastic
pemphigus but also pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP),
disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). SSSS was one of the most
important differential diagnoses in the past, but the incidence is currently very low with 0.09 and 0.13 cases per one
45
million inhabitants per year .

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6. Treatment

6.1. Supportive Care

A critical element of supportive care is the management of fluid, nutrition, and electrolyte requirements.
Intravenous fluid should be given to maintain urine output of 50 - 80 mL per hour with 0.5% NaCl. Supplement was given
with 20 mEq of KCl. Aggressive replacement therapy is required in case of hyponatraemia, hypokalaemia or
hypophosphataemia which quite frequently occur. Wounds should be treated conservatively, without skin debridement
which is often performed in burn units, as skin acts as a natural biological dressing which likely favors re-
48
epithelialization .
6.2. Drug therapy
6.2.1. Systemic steroids
49
A recent study suggests that a short course of high dose corticosteroids (dexamethasone) may be of benefit .
6.2.2. High-dose intravenous immunoglobulins
50
IVIG have been tested for the treatment of TEN and their effect reported in different non-controlled studies . All
51
study confirm the known excellent tolerability and a low toxic potential of IVIG when used with appropriate precaution
in patients with potential risk factors (renal insufficiency, cardiac insufficiency, IgA deficiency, thrombo-embolic
52,53,54
risk) .
6.2.3. Ciclosporin (CsA)
Patients treated with CsA had significantly shorter time to complete re-epithelialisation 55. A small case series with
three TEN patients treated initially with high-doses of intravenous dexamethasone followed by CsA showed a stop in
disease progression within 72 hrs56.
6.3. Treatment for ocular manifestations
Treatment of acute ocular manifestations usually begins with aggressive lubrication of the ocular surface. As
inflammation and changes ensue, most ophthalmologists use topical steroids, antibiotics, and symblepharon lysis. In case
of exposure keratopathy, tarsorrhaphy may be required. Visual rehabilitation in patients with visual impairment can be
considered once the eye has been quiet for at least 3 months.
6.4. Topical treatment
Erosions can be treated with chlorhexidine, octenisept or polyhexanide solutions. The latter is important if
environmental factors, such as high room temperature or alternating pressure mattress, lead to skin dryness. Silver
sulfadiazine should be avoided, at least if the causative drug was cotrimoxazole or another anti-infective sulfonamide.
Some burn care specialists debride the skin under general anesthesia and apply other types of coverage 60.
For affected mucosal surfaces, specialized care is critical. Disinfectant mouth wash should be used to treat oral
erosions and mild ointment, such as dexpanthenol, should be applied on erosions and bloody crusts of the lips.
In the case of eye-involvement, regular ophthalmologic consultation is crucial. Specialized lid care is needed on a
daily basis and anti-inflammatory eye drops should be given several times per day. Severe blepharitis may lead to
entropion with trichiasis (in growing eye lashes) causing further corneal damage. Various specialized approaches to ocular
involvement have been suggested, such as stem cell generation of replacement cells, amniotic membrane transplantation
61,62
and scleral lenses, but are not yet widely accepted .

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7. Conclusion
SJS/TEN is mainly caused by drugs, infections and probably other risk factors not yet identified. The
pathogenesis of SJS/TEN has not been completely solved, but specific genetic predispositions, which vary among ethnic
groups and differ between certain causing drugs, were identified. Despite all therapeutic efforts, mortality is high and
increases with disease severity, patients age and underlying medical conditions. Survivors may suffer from long-term
sequelae such as strictures of mucous membranes including severe eye problems. Therefore, interdisciplinary care and
follow-up of patients with SJS/TEN is important.

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