International Journal of Pharmacological Research

ISSN: 2277-3312

www.ssjournals.com
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 predominantly involve the skin and mucous membranes. They are characterized by mucocutaneous
tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as
blisters and areas of denuded 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 alongside 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's of the oxicam-type. Differential diagnosis includes linear 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 culprit drug, specialized supportive care ideally in an intensive care unit, and consideration 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
involves the skin and the mucous membranes1. Stevens-Johnson syndrome was first described in 1922 as an extraordinary,
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 at opposite ends of the age spectrum, i.e., the
very young and the old, are usually fatal cases. Death is commonly due to infectious complications 2-5.
Toxic epidermal necrolysis (TEN) is usually drug-related6,7. 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,
more than 100 drugs have been implicated as causes of StevensJohnson syndrome or toxic epidermal necrolysis8-13. 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. When there is very extensive skin detachment typical pattern of toxic epidermal
necrolysis. And a poor prognosis (death rates of 30 to 40 percent), the condition is usually called toxic epidermal
necrolysis. Milder forms are known as StevensJohnson syndrome Typical Pattern of StevensJohnson Syndrome or
overlapping Stevens Johnson syndrome and toxic epidermal necrolysis14.
The simplest classification breaks the disease down as follows1 :
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 condition has similarities in clinical presentation to SJS/TEN but has some distinct differences 11,14 as
mentioned in table-1 and figure-1.

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

TEN
>30%
>905
Yes
Flat
50%
Medication
No
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
Mycoplasma pneumonia15,16
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;
ciprofloxacin has also been reported17.
The following anticonvulsants have been implicated:
Phenytoin
Carbamazepine
oxcarbazepine (Trileptal)
Valproic acid
Lamotrigine
Barbiturates
Mockenhapupt et al stressed that most anticonvulsant-induced SJS occurs in the first 60 days of use18.
Antiretroviral drugs implicated in Stevens-Johnson syndrome include nevirapine and possibly other non-nucleoside
reverse transcriptase inhibitors.19
Stevens-Johnson syndrome has also been reported in patients taking the following drugs:
Modafinil (Provigil)
Allopurinol20
Mirtazapine21
TNF-alpha antagonists (eg, infliximab, etanercept, adalimumab)22
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
syndrome upon exposure to specific drugs. HLA-B*5801 confers a risk of allopurinol-related reactions.23 Pretreatment
screening is not readily available.24 Whites with HLA-B*44 appear to be more susceptible to develop Stevens-Johnson
syndrome. 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 to be was strongly
associated with Stevens-Johnson syndrome with ocular disease. 25,26 Nevertheless, whether the presence of those genes
constitutes a predisposition to Stevens-Johnson syndrome or whether those genes are in linkage disequilibrium with more
relevant adjacent genes is unknown. 27

3. Signs and symptoms

Typical prodromal symptoms 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 confluent erythema
The typical lesion has the appearance of a target; this is considered pathognomonic
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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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
Sloughing
Blistering
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 fully understood but is believed to be immune-mediated, as re-challenging an
individual with the same drug can result in rapid recurrence of SJS/TEN 29,29.
An idiosyncratic, delayed hypersensitivity reaction has been implicated in the pathophysiology of StevensJohnson syndrome. Certain population groups appear more susceptible to develop Stevens-Johnson syndrome than the
general population. Slow acetylators, patients who are immunocompromised (especially those infected with HIV 30,31 ), and
patients with brain tumors undergoing radiotherapy with concomitant antiepileptics are among those at most risk. Slow
acetylators are people whose liver cannot completely detoxify reactive drug metabolites. These drug metabolites may have
direct toxic effects or may act as haptens that interact with host tissues, rendering them antigenic. 32,33
Antigen presentation and production of tumor necrosis factor (TNF)alpha by the local tissue dendrocytes results
in the recruitment and augmentation of T-lymphocyte proliferation and enhances the cytotoxicity of the other immune
effector cells.34A "killer effector molecule" has been identified that may play a role in the activation of cytotoxic
lymphocytes.35 The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms,
which include the release of granzyme B and perforin.
Both SJS and TEN are characterised by the detachment of epidermis from the papillary dermis at the epidermaldermal junction, manifesting as a papulomacular rash and bullae as a result of keratinocyte apoptosis36,37. Keratinocyte
apoptosis mediated by cytotoxic T-lymphocytes (CD8) in SJS and TENS is modulated by plasma TNF-alpha and
interferon-gamma, which are increased in patients with SJS and TEN38,39. This process is currently hypothesised to occur
through 3 possible pathways: Fas-Fas ligand interaction; perforin/granzyme B; and granulysin-mediated.38,40-44

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 livid 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 by the development of blisters. 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. In order to rule out
autoimmune blistering diseases, direct immune fluorescence staining should be additionally performed and no
immunoglobulin and/or complement deposition in the epidermis and/or the epidermal-dermal zone should be detected.
5.1. Differential diagnosis
Major differential diagnosis of SJS/TEN are autoimmune blistering diseases, including linear 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 million inhabitants per year45.

6. Treatment
6.1. Prompt withdrawal of culprit drug(s)
Prompt withdrawal of causative drugs should be a priority when blisters or erosions appear in the course of a drug
eruption. Garcia-Doval et al. have shown that the earlier the causative drug is withdrawn, the better the prognosis, and that
patients exposed to causative drugs with long half-lives have an increased risk of dying46. In order to identify the culprit
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drug(s) it is important to consider the chronology of administration of the drug and the reported ability of the drug to
induce SJS/TEN. The chronology of administration of a culprit drug, or time between first administration and development
of SJS/TEN, is between 1 and 4 weeks in the majority of cases. The reported ability or likelihood of a drug be the cause of
SJS/TEN can be found in Pubmed/Medline or other appropriate sources such as the Litt's drug eruption reference
manual47.
6.2. Supportive Care
A critical element of supportive care is the management of fluid and electrolyte requirements. Intravenous fluid
should be given to maintain urine output of 50 - 80 mL per hour with 0.5% NaCl supplemented with 20 mEq of KCl.
Appropriate early and 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 blistered skin acts as a natural biological dressing which likely favors reepithelialization. Non-adhesive wound dressings are used where required, and topical sulfa containing medications should
be avoided48.
6.3. Drug therapy
6.3.1. Systemic steroids
A recent retrospective monocenter study suggests that a short course "pulse" of high dose corticosteroids
(dexamethasone) may be of benefit 49.
6.3.2. High-dose intravenous immunoglobulins
As a consequence of the discovery of the anti-Fas potential of pooled human intravenous immunoglobulins
(IVIG) in vitro50, IVIG have been tested for the treatment of TEN, and their effect reported in different non-controlled
studies. To date, numerous case reports and 12 non-controlled clinical studies containing 10 or more patients have
analyzed the therapeutic effect of IVIG in TEN. All except one study51 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 risk)52. The concomitant administration of corticosteroids or
immunosuppressive agents remains controversial. IVIG has also been applied in a few children with SJS/TEN, and two
non-controlled studies suggest a possible benefit53,54.
6.3.3. Ciclosporin (CsA)
Patients treated with CsA had significantly shorter time to complete re-epithelialisation, and fewer patients with
multi-organ failure and death were observed55. 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. Other single case
reports also reported a positive effect of the use of CsA in TEN 57,58. Recently, Valeyrie-Allanore L conducted an open,
phase II trial to determine the safety and possible benefit of ciclosporin59.
6.4. Treatment for ocular manifestations
Treatment of acute ocular manifestations usually begins with aggressive lubrication of the ocular surface. As
inflammation and cicatricial changes ensue, most ophthalmologists use topical steroids, antibiotics, and symblepharon
lysis. In case of exposure keratopathy, tarsorrhaphy may be required. Maintenance of ocular integrity can be achieved
through the use of amniotic membrane grafting, adhesive glues, lamellar grafts, and penetrating keratoplasty, either in the
acute phase or in subsequent follow-up care. Visual rehabilitation in patients with visual impairment can be considered
once the eye has been quiet for at least 3 months.
6.5. Topical treatment
Although the blisters are fragile, they should be left in place or only be punctured. Erosions can be treated with
chlorhexidine, octenisept or polyhexanide solutions and impregnated nonadhesive mesh gauze. 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 allografts or other types of coverage.
However, this rather aggressive procedure is not tolerated well by many elderly patients with underlying diseases 60.
Furthermore, hypertrophic scars may occur if debridement is carried out extensively and if allografts are fixed with staples
directly into the skin.
For affected mucosal surfaces, specialized care is critical. The severity of the mucosal involvement is often not in
line with the amount of skin detachment and overlooked mucosal lesions can lead to life-long problems. A
multidisciplinary approach is needed and in case of urethral involvement urologists should be involved. Appropriately
placed wet dressings or sitz baths may help to avoid adhesions or strictures of genital erosions in girls and women.
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
and scleral lenses, but are not yet widely accepted61,62. Nevertheless, experienced ophthalmologists should be involved in
the care of all patients with SJS/TEN, even those that do not present with eye-involvement right away, since it may occur
with some delay.
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7. Conclusion
SJS and toxic epidermal necrolysis (TEN) are considered as one disease entity of different severity. 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. Since to date no treatment has been identified to be capable of halting the
progression of skin detachment, supportive management is crucial to improve the patients state, probably more than
specific immunomodulating treatments. 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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