> Table of Contents > Stevens-Johnson Syndrome
Stevens-Johnson Syndrome
Matthew A. Silva, PharmD, RPh, BCPS
Pablo I. Hernandez Itriago, MD, MS, FAAFP
image BASICS
DESCRIPTION
  • A generalized hypersensitivity reaction, usually to a drug, in which skin and mucous membrane lesions are an early manifestation
  • A severe form of erythema multiforme in which >1 mucosal surface is involved; many now consider it to be a different disease with a more difficult course and a more ominous prognosis.
  • Stevens-Johnson syndrome (SJS) exists on a continuum with toxic epidermal necrolysis (TEN).
  • SJS presents with characteristic targetoid cutaneous lesions when <10% of the body surface area (BSA) is involved.
  • Targetoid cutaneous lesion involvement of 10-30% of BSA is considered an overlap between SJS and TEN. Involvement of >30% of BSA is TEN, which has a high morbidity and up to 70% mortality.
  • System(s) affected: cardiovascular, hematologic, lymphatic/immunologic, nervous, renal/urologic, skin/exocrine
  • Synonym(s): ectodermosis erosiva pluriorificialis; febrile mucocutaneous syndrome; herpes iris; erythema polymorphe; toxic epidermal necrolysis (TEN)
Geriatric Considerations
TEN has a greater mortality in older patients.
Pediatric Considerations
Rare in children <3 years of age, more common in years 3 to young adult
Pregnancy Considerations
Pregnancy is a possible predisposing condition.
EPIDEMIOLOGY
Incidence
  • Incidence/prevalence of SJS in the United States is difficult to estimate because there is no universally accepted definition of SJS.
  • 1.1 to 7.1 and 0.4 to 1.2 cases/1 million personyears for SJS and TEN, respectively
Prevalence
  • Predominant sex: male > female (2:1)
  • Sex (females): 33-62% for SJS and 61.3-64.3% for TEN
  • Age (average range): 25 to 47 years for SJS and 46 to 63 years for TEN, <10% of cases are children.
ETIOLOGY AND PATHOPHYSIOLOGY
  • 50% of cases are idiopathic; cross-reactivity between drug classes is suspected (1).
  • Associated with abnormal metabolism and clearance of drugs and metabolites (2)
  • Slow intrinsic acetylation rates
  • 75% of cases involving SJS/TEN including those with overlap associated with a recent medication:
    • 50% of cases occur within 4 weeks and 90% of cases occur within 8 weeks of an offending agent (1).
  • Algorithm-based approach is helpful for assessing probability of drug causality in SJS, TEN, or overlap (3)[B],(4).
  • Frequently associated with upper respiratory tract infection and recent use of antibiotics
  • Sulfonamides are the drugs most strongly associated with SJS and TEN. Then:
    • Cephalosporins
    • Quinolones
    • Aminopenicillins
    • Tetracyclines
    • Macrolides
    • Imidazole antifungals
    • Antiretrovirals (e.g., protease inhibitors, efavirenz, abacavir, amprenavir, telaprevir, fosamprenavir, atazanavir, darunavir, etravirine)
    • Anticonvulsants, especially carbamazepine
    • NSAIDs, especially oxicam
    • Allopurinol, especially in patients of European/Israeli heritage
    • Acetaminophen
    • Vaccines: DPT, BCG, oral polio
    • Mycoplasma pneumoniae infection
  • Erythematous papular lesions and keratinocyte necrosis are a consequence of cell-mediated immunity.
  • Occurs 1 to 2 weeks after initial exposure to offending drugs and within 48 hours on rechallenge
  • Accumulation and binding of reactive drug metabolites to mucocutaneous epithelial cells as haptens (3)
  • Drug haptens signal drug-specific CD8+ T-lymphocyte and macrophages, which infiltrate and express interleukin 2 (IL-2), tumor necrosis factor-&agr; (TNF-&agr;), and interferon-&ggr;, leading to keratinocyte activation.
  • Cytokines enhance keratinocyte expression of soluble Fas ligand and Fas receptors, leading to apoptosis.
Genetics
Associations with HLA-A*3101 in Northern Europeans; HLA-B*1501, HLA-B*1502, HLA-B*1511, HLA-B*5801 in patients of Asian ancestry, HLA-Bw44, HLA-B12, and HLA-DQB1*0601
RISK FACTORS
  • Previous history of SJS
  • Immunocompromised status, including chronic viral infections with Epstein-Barr virus and HIV (5)
  • Patients with HIV infection may be predisposed to developing SJS in response to their medications:
    • HLA allele subtypes A, B, and D
    • Diseases that cause immune compromise (e.g., deficiencies, malignancy)
    • Possibly radiation therapy/ultraviolet light
GENERAL PREVENTION
Secondary prevention possible by avoiding exposure to offending medications/chemical agents.
COMMONLY ASSOCIATED CONDITIONS
  • SJS progressing to TEN is ominous prognostically.
  • M. pneumoniae may be an infectious precursor.
image DIAGNOSIS
PHYSICAL EXAM
  • Recognized by the presence of several of the following features:
    • Vesicles and ulcers on the mucous membranes, especially the mouth and throat
    • Confluent erythematous macules with purpuric, necrotic centers and overlying blistering (1)
    • Epidermal detachment with light lateral pressure (Nikolsky sign)
    • Fever 39-40°C (102-104°F)
    • Crusted nares
    • Conjunctivitis and/or corneal ulcerations
    • Erosive vulvovaginitis/balanitis
    • Cough productive of thick, purulent sputum
    • Tachypnea/respiratory distress
    • Arrhythmias
    • Pericarditis
    • Congestive heart failure (CHF)
    • Mental status changes
    • Seizures
    • Coma
  • Sepsis:
    • May be seen in SJS when epidermal detachment affects <10% of the skin
    • Seen in TEN if epidermal detachment >30% or >10% in the absence of discrete skin lesions
DIFFERENTIAL DIAGNOSIS
  • Erythema multiforme major
  • Exfoliative dermatitis
  • Linear IgA bullous dermatosis
  • Staphylococcal scalded skin syndrome
  • Pemphigus (paraneoplastic)
  • Generalized fixed drug eruption
  • Burns
  • Pressure blisters (coma, barbiturates)
P.989

DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Culture/serologic tests for suspected sources of infection
  • Electrolytes and creatinine
  • Urine for albuminuria/hematuria
Follow-Up Tests & Special Considerations
Skin biopsy
image TREATMENT
GENERAL MEASURES
  • Withdraw all suspected medications, and treat any underlying disease.
  • Meticulous care of damaged skin
  • Supportive care, including moisture-retentive ointment, petroleum jelly, and sterile saline compresses
  • Catheter changing and culturing
  • Reverse isolation and temperature control with extensive epidermal loss
  • Maintenance of fluid, electrolyte, and protein balance
  • Plasmapheresis
  • Adequate calorie intake; parenteral nutrition, if necessary
  • Mouthwashes of warm saline or a solution of diphenhydramine, lidocaine, and kaolin suspension
  • Ophthalmologic consultation and monitoring for corneal damage
  • Venous thromboembolism prophylaxis with unfractionated heparin or low-molecular-weight heparin
MEDICATION
First Line
  • Corticosteroids are controversial. Early high-dose IV steroids may attenuate disease progression, reduce skin detachment, decrease inflammatory cytokine activity, and improve patient comfort. Withdraw if no benefit is seen in the 1st few days.
  • Experimental treatments that appear to have been useful include:
    • Recombinant granulocyte colony-stimulating factor
    • Cyclophosphamide
    • Cyclosporine (6)
    • Intravenous immunoglobulin (IVIG) in HIV-positive patients; IVIG is considered beneficial treatment and prophylaxis, although not approved by the FDA (5). Interferes with Fas ligand-induced apoptosis.
  • Contraindications: Avoid steroids in diabetic/immunosuppressed patients/those with chronic infections.
Second Line
  • Acyclovir for herpetic infections
  • Erythromycin or related antibiotic for Mycoplasma infections (empirical use of antibiotics is not recommended)
ADDITIONAL THERAPIES
In severe ocular surface and eyelid inflammation due to acute SJS and TEN, amniotic membrane transplantation is an effective treatment for severe ocular surface and eyelid inflammation, greatly decreasing the risk of significant ocular and visual sequelae.
SURGERY/OTHER PROCEDURES
  • Sterile débridement of areas of extensive epidermal loss
  • Application of biosynthetic dressings, such as Biobrane to denuded areas
  • Damage to the vulva, vagina, or cornea: Consider surgical repair.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • This disease progresses rapidly; all patients should be admitted.
  • Admission to a burn unit greatly improves the outcome for any patient who has sloughed skin over ≥10% of the BSA.
  • ICU for bronchiolitis, acute respiratory distress syndrome (ARDS), or multiorgan damage
IV Fluids
Fluid management with saline and macromolecules is necessary in the first 24 hours with decreasing IV fluid requirements as oral intake proceeds with nasogastric tube.
Nursing
  • Bed rest until clinically stabilized
  • Avoid administration of topical silver sulfadiazine owing to association with sulfonamide and SJS.
  • Use a coordinated approach involving critical care, wound care, and burn specialists (1).
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Extensive documentation of all offending/suspected medications/chemical agents
  • Education to limit exposure to offending/suspected medications/chemical agents
DIET
IV nutritional support with increased protein requirements; may need insulin for glycoregulation in this hypercatabolic state
PATIENT EDUCATION
Plan to prevent exposure to offending/suspected medications/agents.
PROGNOSIS
  • Rapid onset or evolve over 1 to 2 weeks with resolution over 4 to 6 weeks.
  • Often skin/mucous membrane scarring occurs, especially of the vulva
  • Blindness/corneal opacities occur in 7-20% of patients.
  • Risk of recurrence is as high as 37%.
REFERENCES
1. 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.
2. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens-Johnson syndrome: a review. Crit Care Med. 2011;39(6):1521-1532.
3. Pichler WJ, Naisbitt DJ, Park BK. Immune pathomechanism of drug hypersensitivity reactions. J Allergy Clin Immunol. 2011;127(3 Suppl): S74-S81.
4. 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;88(1):60-68.
5. Hazin R, Ibrahimi OA, Hazin MI, et al. Stevens-Johnson syndrome: pathogenesis, diagnosis, and management. Ann Med. 2008;40(2):129-138.
6. Reese D, Henning JS, Rockers K, et al. Cyclosporine for SJS/TEN: a case series and review of the literature. Cutis. 2011;87(1):24-29.
7. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;84(6): 803-813.
See Also
&NA;
Burns; Cutaneous Drug Reactions; Dermatitis Herpetiformis; Erythema Multiforme; Pemphigoid, Bullous; Pemphigus Vulgaris; Respiratory Distress Syndrome, Acute (ARDS)
Codes
&NA;
ICD10
  • L51.1 Stevens-Johnson syndrome
  • L51.3 Stevens-Johnson synd-tox epdrml necrolysis overlap syndrome
Clinical Pearls
&NA;
  • Corticosteroid treatment is controversial. If chosen and no response within 1st few days, discontinue.
  • Recurrences are possible. Etiologic agents should be identified if possible and avoided indefinitely.