Stevens Johnson Syndrome & Toxic Epidermal Necrolysis

Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are now believed to be variants of the same condition, distinct from erythema multiforme. SJS/TEN is a very rare, acute, serious, and potentially fatal skin reaction in which there is sheet-like skin and mucosal loss. Using current definitions, it is usually, possibly always, caused by medications.

Who gets SJS/TEN?

Fortunately SJS/TEN is a very rare complication of medication use (estimated to be 1-2/million each year for SJS, and 0.4-1.2/million each year for TEN). But anyone on medication can develop SJS/TEN unpredictably. It can affect all age groups, both sexes and all races. It is more common in association with human immunodeficiency virus infection (HIV), which may reflect the increased use of medications by HIV patients.

More than 200 medications have been reported in association with SJS/TEN. It is more often seen with drugs with long half-lives compared to even a chemically similar related drug with a short half-life. A half-life of a medication is the time that half of the delivered dose remains circulating in the body.

The most commonly implicated medications are antibacterial sulfonamides.

Drugs that most commonly cause SJS/TEN

Antibiotics Antifungals Antivirals	Sulfonamides, e.g., cotrimoxisole; beta-lactams i.e., penicillins, cephalosporins Imidazole antifungals Nevirapine (non-nucleoside reverse-transcriptase inhibitor)
Allopurinol
Nonsteroidal anti-inflammatory drugs (NSAID) (oxicam type mainly)	Naproxen Ibuprofen
Anti-convulsants	Carbamazepine Phenytoin Phenobarbital Valproic acid Lamotrigine

The adverse drug reaction SJS/TEN usually develops within the first week of antibiotic therapy but up to 2 months after starting an anticonvulsant. For most drugs the onset is within a few days up to 1 month.

Clinical features of SJS/TEN

Before the rash appears, there is usually a prodromal illness of several days duration resembling an upper respiratory tract infection or 'flu-like illness. Symptoms may include:

• Fever – persistent and high
• Cough
• Sore throat, difficulty swallowing
• Runny nose
• Sore red eyes, conjunctivitis
• General aches and pains.

There is then an abrupt onset of a tender/painful red skin rash starting on the trunk and extending rapidly over hours to days onto the face and limbs. The maximum extent is usually reached by 4 days. The skin lesions may be:

• Macules – flat, red and diffuse (measles-like) or purple (purpuric) spots
• Targets – as in erythema multiforme
• Blisters – flaccid (ie not tense)

The blisters then merge to form sheets of skin detachment, exposing red, oozing dermis. The Nikolsky sign is positive in areas of skin redness. This means that blisters appear when the skin is rubbed gently.

Skin signs in SJS/TEN

Mucosal involvement is prominent and severe, although not forming actual blisters. At least 2 mucosal surfaces are affected including:

• Eyes (conjunctivitis) – red, sore, sticky
• Lips/mouth (cheilitis, stomatitis) – red crusted lips, mouth ulcers
• Oesophagus – causing difficulty eating
• Upper respiratory tract (trachea and bronchi) – causing cough and respiratory distress
• Genital area and urinary tract – ulcers
• Gastrointestinal tract – causing diarrhoea.

Mucosal involvement in SJS/TEN

The patient is very ill, extremely anxious and in considerable pain. In addition to skin/mucosal involvement, other organs may be affected including liver, kidneys, lungs, bone marrow and joints.

How is the diagnosis made?

The diagnosis is suspected clinically and classified based on the skin surface area detached at maximum extent.

Classification of TEN

SJS	Skin detachment <10% of body surface area (BSA) Widespread erythematous or purpuric macules or flat atypical targets
Overlap SJS/TEN	Detachment between 10% and 30% of BSA Widespread purpuric macules or flat atypical targets
TEN with spots	Detachment >30% of BSA Widespread purpuric macules or flat atypical targets
TEN without spots	Detachment of >10% of BSA Large epidermal sheets and no purpuric macules

As these areas of skin detachment are at maximum extent, the category cannot always be defined with certainty on initial presentation. The diagnosis may therefore change during the first few days in hospital.

Skin biopsy is usually required to confirm the clinical diagnosis and to exclude Staphylococcal Scalded Skin Syndrome (SSSS) and other generalised rashes with blisters.

The histopathology shows keratinocyte necrosis (death of individual skin cells), full thickness epidermal/epithelial necrosis (death of an entire layer of skin), minimal inflammation (very mild lymphocytic infiltrate of the superficial dermis). The direct immunofluoresence test on the skin biopsy is negative, indicating the disease is not due to deposition of antibodies in the skin.

Blood tests do not help to make the diagnosis but are essential to make sure fluid and vital nutrients have been replaced, to identify complications and to assess prognostic factors (see below). Abnormalities may include:

• Anaemia occurs in virtually all cases (reduced haemoglobin).
• Leucopenia (reduced white cells), especially lymphopenia (reduced lymphocytes) is very common (90%).
• Neutropenia (reduced neutrophils), if present, is a bad prognostic sign.
• Eosinophilia (raised eosinophil count) and atypical lymphocytosis (odd-looking lymphocytes) do not occur.
• Mildly raised liver enzymes is common (30%) and approximately 10% develop overt hepatitis.
• Mild proteinuria (protein leaking into urine) occurs in about 50%. Some changes in kidney function occur in the majority.

Patch testing rarely identifies the culprit in SJS/TEN following recovery, and is not recommended.

What is SCORTEN?

SCORTEN is an illness severity score that has been developed to predict mortality in SJS and TEN cases. One point is scored for each of seven criteria present at the time of admission. The SCORTEN criteria are:

• Age >40 years
• Presence of a malignancy (cancer)
• Heart rate >120
• Initial percentage of epidermal detachment >10%
• Serum urea level >10 mmol/L
• Serum glucose level >14 mmol/L
• Serum bicarbonate level <20 mmol/L

The risk of dying from SJS/TEN depends on the score.

SCORTEN predicted mortality rates

SCORTEN 0-1	>3.2%
SCORTEN 2	>12.1%
SCORTEN 3	>35.3%
SCORTEN 4	>58.3%
SCORTEN 5 or more	>90%

Treatment

Care of a patient with SJS/TEN requires:

• Cessation of suspected causative drug(s) – the patient is less likely to die and complications are less if the culprit drug is stopped no later than the day that blisters/erosions appear
• Hospital admission – preferably immediately to an intensive care and/or burns unit as this improves survival, reduces infection and shortens hospital stay
• Nutritional and fluid replacement by intravenous and nasogastric routes – reviewed and adjusted daily
• Temperature maintenance – as body temperature regulation is impaired
• Pain relief – as pain can be extreme
• Skin care:
  • topical antiseptics e.g. silver nitrate or chlorhexidine, (but not silver sulfadiazine as it is a sulfa drug)
  • dressings such as gauze with petrolatum
  • avoid using adhesive tapes
  • preferable not to remove the dead skin; leave the blister roof as a ‘biological dressing’
• Eye care:
  • daily assessment by ophthalmologist,
  • frequent eye drops/ointments (antiseptic, antibiotic, cortisone)
• Mouth care
• Lung care:
  • may include aerosols, bronchial aspiration, physiotherapy
  • may require intubation and mechanical ventilation if trachea and bronchi are involved
• Urinary catheter because of genital involvement and immobility
• Psychiatric support for extreme anxiety and emotional lability
• Physiotherapy to maintain joint movement and reduce risk of pneumonia
• Regular assessment for infection including of skin, mucous membranes, catheter sites:
  • Staphylococcal infection is common; gram negative infection may also arise
  • appropriate antibiotic should be given if infection develops
  • prophylactic antibiotics are not recommended and may even increase the risk of sepsis

Case reports and small patient series using active adjuvant treatments including ciclosporin, cyclophosphamide, intravenous immunoglobulin (IVIG) and plasmapheresis have reported variable responses. As this is fortunately a rare condition, controlled trials of therapies in large numbers of patients is difficult.

The role of systemic corticosteroids (cortisone) remains controversial. Studies giving high doses of corticosteroids for a short time at the start of the reaction have been shown them to be beneficial. However concerns have been raised that they may increase the risk of infection, impair wound healing and other complications.

Thalidomide, trialled because of its anti-tumour necrosis factor alpha effect, increased mortality, and should not be used.

Some units recommend using heparin routinely to prevent thromboembolism (blood clots).

Specialised nursing care is essential as is frequent reassessment with appropriate adjustments in care.

Complications of SJS/TEN

This condition can be fatal due to complications in the acute phase. The mortality rate is up to 10% for SJS and at least 30% for TEN.

During the acute phase, potentially fatal complications include:

• Dehydration and acute malnutrition
• Infection of skin, mucous membranes, lungs (pneumonia), septicaemia (blood poisoning)
• Shock and multiple organ failure including kidney failure
• Thromboembolism and disseminated intravascular coagulopathy

Longterm complications include:

• Pigment change – patchwork of increased and decreased pigmentation
• Skin scarring, especially at sites of pressure or infection
• Loss of nails with permanent scarring (pterygium) and failure to regrow
• Joint contractures
• Scarred genitalia – phimosis (constricted foreskin which cannot retract) and vaginal synechiae (occluded vagina)
• Serious eye problems, which can lead to blindness. This is the most important of the longterm complications. These include:
  • Dry and/or watery eyes, which may burn and sting when exposed to light
  • Conjunctivitis: red, crusted, or ulcerated conjunctiva
  • Corneal ulcers, opacities and scarring
  • Symblepharon: adhesion of conjunctiva of eyelid to eyeball
  • Ectropion or entropion: turned-out or turned-in eyelid
  • Trichiasis: inverted eyelashes
  • Synechiae: iris sticks to cornea

It may take weeks to months for symptoms and signs to settle.

Complications of SJS/TEN

Dyspigmentation

Nail shedding

Symblepharon

Proposed mechanism

SJS/TEN is a rare and unpredictable reaction to medication. The mechanism has still not been understood and is complex.

1. Drug specific CD8+ cytotoxic lymphocytes can be detected in the early blister fluid. They have some natural killer cell activity and can probably kill keratinocytes by direct contact.
2. Cytokines implicated include perforin/granzyme, Fas-L and Tumour Necrosis Factor (TNF) alpha.

There are probably two major pathways involved:

1. Fas-Fas ligand pathway of apoptosis has been considered a pivotal step in the pathogenesis of TEN. The Fas ligand (FasL), a form of tumour necrosis factor, is secreted by blood lymphocytes and can bind to the Fas ‘death’ receptor expressed by keratinocytes.
2. Granule-mediated exocytosis via perforin and granzyme B resulting in cytotoxicity (cell death). Perforin and granzyme B can be detected in early blister fluid and it has been suggested that levels may be associated with disease severity.

Draft 18 September 2009