Stevens-Johnson Syndrome

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Stevens-Johnson syndrome (SJS) is an immune-complex-mediated hypersensitivity disorder. It ranges from mild skin and mucous membrane lesions to a severe, sometimes fatal systemic illness: toxic epidermal necrosis (TEN). SJS, SJS/TEN overlap and TEN form a spectrum of severe cutaneous adverse reactions (SCAR) that can be differentiated by the degree of skin and mucous membrane involvement. They are mainly, but not always caused by drugs.  Erythema multiforme (EM) was previously considered to be a milder form of SJS without mucosal involvement; however, the clinical classification defined by Bastuji-Garin in 1993 separates EM as a clinically and aetiologically distinct disorder and has now been accepted by consensus.[1][2][3]

The classification published by Bastuji-Garin in 1993, is based on the type of single lesions, and the extent of blisters and erosions on the body surface area (BSA).[1] 

    EMM SJS

SJS/TEN overlap

TEN with spots

TEN
without
spots

Type of lesion    

Typical targets

         

Atypical
targets

Raised

       

Flat

   

 Macules

 

 Erythematous

       

Purpuric

   
Distribution of lesions   Localised          
  Widespread             
Extent of epidermal detachment     <10% <10% 10-30% >30% >10% sheets of epidermal detachment

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Over a period of 20 years, Bastuj's classification has successfully been in several large epidemiological studies (including RegiSCAR) which have provided reliable information on the incidence of SJS and TEN.[3]

  • Incidence is estimated at 2-3 cases/million population/year in Europe.[4].
  • It is much more common in individuals with HIV. (Estimated 1-2/1,000 in Canada.)[5] 
  • It is more common in females than in males.[4]
  • Most patients are aged 10-30 but cases have been reported in children as young as 3 months.

Risk factors

The rarity of the disease has made it difficult to clearly ascertain specific risk factors among heterogeneous populations; however, the presence of particular HLA alleles has been found to be associated with SJS/TEN among particular groups - for example:

  • HLA B1502 and HLA B1508 among the Han Chinese have been found to be associated with SJS/TEN in reaction to carbamazepine and allopurinol respectively.
  • HLAb 5701 abacavir associated with SJS/TEN among people living with HIV.

Screening for these genes among specific populations, before commencing medications, may help to avert occurrence of the disease among these groups.[6] 

Approximately 75% of SJS/TEN are caused by medications, and 25% by infections and 'other' causes.

Drugs most commonly associated with SJS and TEN

  • Allopurinol
  • Carbamazepine
  • Sulfonamides:
    • Trimethoprim-sulfamethoxazole.
    • Sulfadiazine.
    • Sulfasalazine.
  • Antiviral agents:
    • Nevirapine.
    • Abacavir.
  • Anticonvulsants:
    • Phenobarbital.
    • Phenytoin.
    • Valproic acid.
    • Lamotrigine.
  • Others:
    • Imidazole antifungal agents.
    • Non-steroidal anti-inflammatory drugs (oxicam type such as meloxicam).
    • Salicylates.
    • Sertraline.

Infection

Immunisation

Associated with immunisation - eg, measles, hepatitis B.

See images available under 'Further reading' section, below.

Symptoms

  • It often starts with a nonspecific upper respiratory tract infection, which may be associated with fever, sore throat, chills, headache, arthralgia, vomiting and diarrhoea, and malaise.
  • Mucocutaneous lesions develop suddenly and clusters of outbreaks last from 2-4 weeks. The lesions are usually not pruritic.
  • Mouth: severe oromucosal ulceration.
  • Respiratory involvement may cause a cough productive of a thick purulent sputum.
  • Patients with genitourinary involvement may complain of dysuria or an inability to pass urine.
  • Ocular symptoms: painful red eye, purulent conjunctivitis, photophobia, blepharitis.

Signs

  • General examination: fever, tachycardia, hypotension; altered level of consciousness, seizures, coma.
  • Skin:
    • Lesions may occur anywhere, but most commonly affect the palms, soles, dorsum of hands and extensor surfaces. The rash may be confined to any one area of the body, most often the trunk.
    • The rash can begin as macules that develop into papules, vesicles, bullae, urticarial plaques, or confluent erythema.
    • The centre of the lesions may be vesicular, purpuric, or necrotic.
    • The typical lesion has the appearance of a target, which is considered pathognomonic.
    • Lesions may become bullous and later rupture. The skin becomes susceptible to secondary infection.
    • Urticarial lesions are usually not pruritic.
    • Nikolsky sign positive (mechanical pressure to skin leading to blistering within minutes or hours).
  • Mucosal involvement: erythema, oedema, sloughing, blistering, ulceration and necrosis.
  • Eye: conjunctivitis, corneal ulcerations.
  • Genital: erosive vulvovaginitis or balanitis.
  • Serum electrolytes, glucose and bicarbonate are essential to assess clinical severity and level of dehydration.[8]
  • Diagnosis is based on clinical classification - as in the table, above - and on histopathology.
  • Skin biopsy: demonstrates that the bullae are subepidermal. Epidermal cell necrosis may be seen and perivascular areas are infiltrated with lymphocytes.

Multidisciplinary management of eyes, mucous membranes (gynae, mouth, gastrointestinal tract) helps to improve outcomes and reduce adverse sequelae.

  • Acute phase
    • identify and remove causative drug or underlying cause
    • Use of the ALDEN (= Algorithm for assessment of Drug-induced Epidermal Necrosis) may be useful.[10]
  • A rapid assessment of prognosis should be made using the Score for Toxic Epidermal Necrolysis (SCORTEN) system. SCORTEN is an illness severity score which has been developed to predict the mortality rate in SJS and TEN. One point is given for each of seven criteria present at the time of admission. The seven criteria are:
    • Age >40.
    • Presence of malignancy.
    • Heart rate >120 beats per minute.
    • Initial percentage of epidermal detachment >10%.
    • Serum bicarbonate <20 mmol/L.
    • Serum urea >10 mmol/L.
    • Serum glucose >14 mmol/L.
  • Patients with a SCORTEN score of >3 should be managed in intensive care.
  • Supportive:
    • Attention to airway and haemodynamic stability.
    • Severe fluid loss may require intravenous fluid replacement and electrolyte correction.
    • Pain control.
    • Skin lesions are treated in the same way as for burns.
    • Mouth: mouthwashes; topical anaesthetics are useful in reducing pain and allowing the patient to take in fluids..
  • Treat secondary infections.
  • Immunomodulation:
    • The use of corticosteroids is controversial due to the need to balance dampening of the aberrant immune response with poor healing and increased risk of infection. Some progress has been made with the use of pulsed systemic corticosteroids.
    • Some have advocated cyclophosphamide, plasmapheresis, haemodialysis and immunoglobulin therapy, but none of those should be considered standard at this time.[3][11]

Some reports have found early administration of high-dose intravenous immunoglobulin to be associated with increased mortality in SJS and TEN, and so this in no longer recommended.[3] 

  • Gastrointestinal and respiratory involvement may progress to necrosis.
  • Skin: secondary infection and scarring.
  • Mucosal pseudomembrane formation may lead to mucosal scarring and loss of function of the involved organ system.
  • Extensive involvement of the oesophagus may cause oesophageal strictures.
  • Lung: mucosal shedding in the tracheobronchial tree may lead to respiratory failure.
  • Eye complications: include corneal ulceration and anterior uveitis. Blindness may develop secondary to severe keratitis or panophthalmitis in 3-10% of patients.
  • Vaginal stenosis and penile scarring have been reported.
  • Renal complications are uncommon but renal tubular necrosis and renal failure may occur.

Many patients surviving SJS and more that 50% surviving TEN suffer long-term sequelae involving the skin, mucous membranes or eyes. These include:

  • Skin: hyperhidrosis, xeroderma, reversible hair loss, heat and cold sensitivity, scarring and irregular pigmentation.
  • Nails dystrophy.
  • Mucous membranes: vaginal, urethral and anal strictures. Persistent mucosal erosions.
  • Ocular: xerophthalmia, photophobia, symblepharon, synechiae, entropion, meibomian gland dysfunction and blindness.

The mortality rate may be predicted using the SCORTEN score system:

  • 0-1-3.2%
  • 2-12.1%
  • 3-35.3%
  • 4-58.3%
  • >5-90%
  • Future avoidance of any possible or confirmed underlying cause.[6]
  • Screening for particular HLA alleles in particular groups.

Further reading & references

  1. Bastuji-Garin S, Rzany B, Stern RS, et al; Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993 Jan;129(1):92-6.
  2. Becker DS; Toxic epidermal necrolysis. Lancet. 1998 May 9;351(9113):1417-20.
  3. Mockenhaupt M; The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011 Nov;7(6):803-13; quiz 814-5.
  4. Fritsch P; European Dermatology Forum: skin diseases in Europe. Skin diseases with a high public health impact: toxic epidermal necrolysis and Stevens-Johnson syndrome. Eur J Dermatol. 2008 Mar-Apr;18(2):216-7.
  5. Mittmann N, Knowles SR, Koo M, et al; Incidence of toxic epidermal necrolysis and Stevens-Johnson Syndrome in an HIV cohort: an observational, retrospective case series study. Am J Clin Dermatol. 2012 Feb 1;13(1):49-54. doi: 10.2165/11593240-000000000-00000.
  6. Phillips EJ, Chung WH, Mockenhaupt M, et al; Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol. 2011 Mar;127(3 Suppl):S60-6.
  7. Mockenhaupt M, Viboud C, Dunant A, et al; Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008 Jan;128(1):35-44. Epub 2007 Sep 6.
  8. Harr T, French LE; Stevens-Johnson syndrome and toxic epidermal necrolysis. Chem Immunol Allergy. 2012;97:149-66. Epub 2012 May 3.
  9. Guerry MJ, Lemyze M; Acute skin failure. BMJ. 2012 Aug 6;345:e5028. doi: 10.1136/bmj.e5028.
  10. Sassolas B, Haddad C, Mockenhaupt M, et al; ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: comparison with case-control analysis. Clin Pharmacol Ther. 2010 Jul;88(1):60-8. Epub 2010 Apr 7.
  11. Ghislain PD, Roujeau JC; Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome. Dermatol Online J. 2002 Jun;8(1):5.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Colin Tidy
Current Version:
Peer Reviewer:
Dr Adrian Bonsall
Last Checked:
02/11/2012
Document ID:
2801 (v24)
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