BASICS
DESCRIPTION
• Stevens–Johnson syndrome (SJS) was first described in 1922.
• SJS is a rare life-threatening immune complex–mediated hypersensitivity reaction in which the skin and mucous membranes are severely affected.
• SJS is often referred to as erythema multiforme major or bullous erythema multiforme.
EPIDEMIOLOGY
Incidence
• The reported annual incidence of SJS is approximately 3 cases per million persons per year.
• In the US, approximately 300 new cases of SJS are reported each year.
Prevalence
The prevalence of SJS is reported to be less than 200,000 persons in the US population.
RISK FACTORS
• Immunocompromised status, including malignancies, chronic viral infections with Epstein–Barr virus (EBV) and HIV, systemic lupus erythematosus, and other chronic rheumatologic diseases are considered risk factors.
• Radiation therapy and ultraviolet (UV) light are also considered possible risk factors.
• Previous history of SJS is considered a risk factor for further episodes.
Genetics
Certain HLA subtypes are currently being researched for possible associations with SJS. In some studies, HLA-B12 has been shown to increase susceptibility to SJS.
GENERAL PREVENTION
Early diagnosis, treatment, and supportive therapy are essential to prevent life-threatening complications and permanent damage from SJS.
PATHOPHYSIOLOGY
• SJS is an immune complex–mediated hypersensitivity reaction.
• Cell death causes separation of the epidermis from the dermis.
ETIOLOGY
• Although the cause of SJS may not be determined in some case, it is most often a response to medication, infection, or illness.
• SJS is idiopathic in approximately 50% of the cases.
• The leading cause of SJS is the use of antibiotics and sulfa drugs. Some of the common medications that cause SJS include allopurinol, diclofenac, isotretinoin, fluconazole, penicillins, barbiturates, sulfonamides, phenytoin, and azithromycin.
• Infectious causes of SJS include herpes simplex virus, EBV, influenza, mumps, histoplasmosis, and cat scratch fever.
• Certain lymphomas and carcinomas have also been reported to be the inciting factors for SJS.
• In some studies, herbal supplements containing ginseng have been shown to cause SJS as a rare side effect. Others report cocaine as a possible cause.
COMMONLY ASSOCIATED CONDITIONS
SJS can involve the mucous membrane and skin of multiple organs. Significant involvement of ocular, nasal, oral, vaginal, urethral, gastrointestinal, and respiratory tract mucous membranes can occur over the course of the disease. Necrosis of mucous membranes, especially respiratory and gastrointestinal membranes, may occur over the course of the disease. This can lead to significant morbidity and may lead to death.
DIAGNOSIS
HISTORY
• SJS often begins with flu-like symptoms. Patients may often experience fever, malaise, cough, sore throat, headache, and burning eyes for a few days. Mucocutaneous lesions develop abruptly.
• Patients with oral involvement may complain of severe pain that leads to inability to eat or drink.
• Patients with genitourinary tract involvement may present with dysuria or inability to void.
PHYSICAL EXAM
• Ophthalmic findings:
– Conjunctivitis of the eyes is reported in approximately 30%.
– Conjunctival scarring, including symblepharon formation may occur.
– Pseudomembranes may form on palpebral conjunctiva.
– Dry eyes and trichiasis are chronic sequelae.
– Corneal neovascularization, corneal scarring, anterior uveitis, panuveitis, and severe visual impairment may occur.
• Systemic findings:
– Patients may often get tongue and facial swelling.
– Oral ulcers are common, but ulcers of genital and anal areas may also occur.
– Skin involvement may start with hives and pain. A red or purple skin nonpruritic rash develops and spreads within hours to days. Papules, vesicles, or bullae may form leading to sloughing of the epidermis. The typical skin lesion of SJS is target shaped. Most commonly affected areas are the palms, soles, dorsum of the hands, and extensor surfaces.
– Denuded skin may develop a secondary infection.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Although SJS may often be medication induced, it is important to rule out infectious etiologies and malignancies.
• Blood and urine cultures should be done in cases where an infectious cause is suspected.
• Sputum cultures should be done in patients with a high index of suspicion for Mycoplasma pneumoniae.
• HIV and EBV testing should be done in patients suspected of these diseases.
• CBC count and workup of malignancy should be performed.
• A tissue biopsy is performed in many cases.
Imaging
Imaging is rarely required, except in cases where a malignancy is suspected.
Pathological Findings
• Biopsy specimens typically show full thickness necrosis of epidermis and minimal dermal inflammatory cell infiltration. The dermal infiltrate is superficial and mostly perivascular.
• Histologic changes in the epidermal–dermal junction range from vacuolar alteration to subepidermal blisters.
• Apoptosis of keratinocytes is also observed.
DIFFERENTIAL DIAGNOSIS
• Erythema multiforme minor (involvement of skin only. SJS, or erythema multiforme major, is defined as involvement of both skin and mucous membranes. SJS is often referred to as bullous erythema multiforme.)
• Drug rash
• Thermal burns
• Paraneoplastic pemphigus
• Toxic shock syndrome
• Ocular cicatricial pemphigoid
• Toxic epidermal necrolysis (TEN) (SJS and TEN are considered similar except for their distribution. SJS is defined as <10% of body surface area involvement. TEN is defined by >30% of body surface area involvement. Involvement of 15–30% of body surface area is considered SJS–TEN overlap.)
TREATMENT
MEDICATION
First Line
• SJS is a dermatologic emergency that requires hospitalization, often in an intensive care unit or burn unit.
• Often the first and most important step in treating SJS is to discontinue any offending medications.
• Supportive care is a crucial part of treating SJS. Because skin loss can lead to significant loss of body fluid, fluid replacement is essential. A nasogastric tube may be needed for enteral feedings.
• Ophthalmic care should include a thorough eye exam. If a patient has conjunctivitis, pseudomembranes, or other ocular surface disease, topical steroids should be used judiciously. Pseudomembranes should be peeled. Symblepharon should be lysed using a blunt instrument such as a glass rod. A symblepharon ring should be placed to avoid further symblepharon formation. Oral or intravenous corticosteroids should be considered in patients with ocular disease. Patients with uveitis should be treated with steroids.
Second Line
• Skin lesions should be cleaned thoroughly and protected from secondary infections.
• Patients with SJS often have severe pain from mucocutaneous lesions and should be given adequate pain control.
• Intravenous steroids are used by many in acute SJS. In cases of recalcitrant SJS, intravenous immunoglobulin has been proposed by some to be beneficial.
• Cyclophosphamide may be used in chronic conditions.
• Patients on steroids should be placed on gastrointestinal prophylaxis and should be considered at risk for bone mass loss.
ADDITIONAL TREATMENT
General Measures
• Early diagnosis and treatment are crucial to decreasing morbidity and mortality in patients with SJS.
• Patients should be monitored closely to avoid sepsis, shock, and organ failure.
Issues for Referral
Dermatologists and ophthalmologists are consulted for patients with SJS. Specialists are consulted according to the organs involved.
IN-PATIENT CONSIDERATIONS
Initial Stabilization
• SJS is a medical emergency that can rapidly evolve into shock and end-organ damage/failure.
• Treatment should focus on eliminating the underlying cause, controlling symptoms, and minimizing complications.
Admission Criteria
Patients with SJS can rapidly develop shock and end-organ failure and should be monitored very closely.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
• Patients have to be monitored very closely in the initial stages of SJS.
• Patients should be monitored closely by an ophthalmologist as symblepharon formation, trichiasis, corneal neovascularization, and scarring can develop.
Patient Monitoring
• CBC count should be performed weekly for the first 1–2 months in patients on oral cyclophosphamide to evaluate for leukopenia.
• Urinalysis should be performed periodically to evaluate for hemorrhagic cystitis.
DIET
Many patients have difficulty swallowing in the initial stages of SJS secondary to involvement of the gastrointestinal tract. Enteral feeding may be required until the patient can tolerate oral feedings.
PATIENT EDUCATION
• Patients should be advised of the inciting factor (medication, infection, etc.) and should be told to avoid the inciting factor.
• Patients should be informed of the increased risk of SJS with the use of certain medications.
PROGNOSIS
The mortality in patients with SJS correlates to the body surface area involved. If less than 10% of the body surface is denuded, the mortality rate is approximately 1–5%. If more than 30% of the body surface is denuded, the mortality rate increases to more than 25%.
REFERENCES
1. Wetter DA, Camilleri MJ. Clinical, etiologic, and histopathologic features of Stevens-Johnson syndrome during an 8-year period at Mayo Clinic. Mayo Clin Proc 2010;85(2):131–138.
2. Sotozono C, Ueta M, Kinoshita S. Systemic and local management at the onset of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications. Am J Ophthalmol 2010;149(2):354.
3. Knowles S, Shear NH. Clinical risk management of Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Dermatol Ther 2009;22(5):441–451.
4. Struck MF, Hilbert P, Mockenhaupt M, et al. Severe cutaneous adverse reactions: emergency approach to non-burn epidermolytic syndromes. Intensive Care Med 2010;36(1):22–32. Epub 2009 Sep 29.
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