eMedicine Specialties > Ophthalmology > Dermatologic Disorders
Stevens-Johnson Syndrome
Updated: Dec 18, 2007
Introduction
Background
In 1922, Stevens and Johnson first described 2 patients, boys aged 7 and 8 years, with "an extraordinary, generalized eruption with continued fever, inflamed buccal mucosa, and severe purulent conjunctivitis." Both cases were misdiagnosed by primary care physicians as hemorrhagic measles. Erythema multiforme (EM), originally described by von Hebra in 1866, was part of the differential diagnosis in both cases, but it was excluded because of the "character of skin lesions, the lack of subjective symptoms, the prolonged high fever, and the terminal heavy crusting." In spite of leukopenia in both cases, Stevens and Johnson in their initial report suspected an infectious disease of unknown etiology as the cause.
In 1950, Thomas divided EM into 2 categories, as follows: erythema multiforme minor (von Hebra) and erythema multiforme major (EMM; also known as Stevens-Johnson syndrome, or SJS). Since 1983, the eponym of Stevens-Johnson syndrome had been used as a synonym for EMM.
In the 1990s, Bastuji and Roujeau each proposed that EMM and SJS are 2 distinct disorders.1 They suggested that the denomination of EM should be restricted to patients with typical targets or raised edematous papules, with or without mucosal involvement. This clinical picture is in accordance with the original description by von Hebra. They further proposed that the denomination of SJS should be used for a syndrome characterized by mucous membrane erosions and widespread small blisters that arise on erythematous or purpuric maculae that are different from classic targets. According to this clinical classification, EMM and SJS could be 2 distinct disorders with similar mucosal erosions, but different patterns of cutaneous lesions. This hypothesis is supported further by a strong correlation between clinical classification and the probable cause.
Conversely, several investigators propose that SJS and toxic epidermal necrolysis (TEN) are the same diseases of various severities. It has been suggested to use a unifying classification of "acute disseminated epidermal necrosis" or "exanthematic necrolysis." A very strong argument against this unifying concept was that infection with herpes simplex virus (HSV) had been described as a frequent cause of SJS/EMM but not of TEN. However, reports showed that HSV infection has not been related to SJS, and they suggested that SJS and TEN, based on clinical manifestations and pathology results, are severity variants of the same disease, which differ from EM.
SJS and TEN are characterized by identical clinical signs and symptoms, identical treatment approach, and identical prognosis. Patients with 90% skin detachment and diagnosed with TEN may have none or only mild ocular involvement with excellent prognosis quod visum, and patients with 10% skin detachment may have severe ocular involvement with blinding consequences, and vice versa.
Pathophysiology
An idiosyncratic, delayed hypersensitivity reaction has been implicated in the pathophysiology of SJS. Certain groups of patients appear more susceptible to develop SJS than the general population. The slow acetylators, patients who are immunocompromised, and patients with brain tumors undergoing radiotherapy with concomitant antiepileptics are among those at most risk. The slow acetylators are incapable of achieving complete detoxification of reactive drug metabolites. Such metabolites can act as haptens that interact with host tissues rendering them to be antigenic.2,3
Antigen presentation and production of tumor necrosis factor alpha (TNF-alpha) by the local tissue dendrocytes results in the recruitment and augmentation of T-lymphocytes' proliferation and enhances the cytotoxicity of the other immune effector cells.4 The activated CD8+ lymphocytes, in turn, can induce epidermal cell apoptosis via several mechanisms, which include the release of granzyme B and perforin. Apoptosis of the keratinocytes can also take place as a result of ligation of their surface death receptors with the appropriate molecules. Those can trigger the activation of the caspase system leading to DNA disorganization and cell death.5
Apoptosis of the keratinocytes can be mediated via direct interaction between the cell-death receptor Fas and its ligand. Both can be present on the surfaces of the keratinocytes. Alternatively, activated T-cells can release soluble Fas ligand and interferon-gamma, which induces Fas expression by the keratinocytes.6
Once apoptosis ensues, the dying cells provoke recruitment of more chemokines; this can perpetuate the inflammatory process, which leads to extensive epidermal necrolysis.7
Frequency
United States
The incidence of SJS is estimated to be 2.6-7.1 cases per 1 million person-years.
International
A study from Germany reports 1.1 cases per 1 million person-years.
Mortality/Morbidity
The mortality rate has been reported to be 1-3%.
Race
SJS can occur in all races worldwide.
Sex
The proportion of females has been estimated to be 33-62%. The largest series reports 39.9% of females in a group of 315 patients with SJS.
Age
In a large cohort, the mean age of patients with SJS is 25 years. In a smaller series, the mean age of patients with SJS has been reported as 47 years.
Clinical
History
- Ocular symptoms
- Red eye
- Tearing
- Dry eye
- Pain
- Blepharospasm
- Itching
- Grittiness
- Heavy eyelid
- Foreign body sensation
- Decreased vision
- Burn sensation
- Photophobia
- Diplopia
- Other symptoms
- Skin lesions
- Oral lesions
- Esophageal lesions
- Pharyngeal lesions
- Laryngeal lesions
- Anal lesions
- Tracheal lesions
- Vaginal lesions
- Urethral lesions
Physical
- External examination
- Conjunctival hyperemia (ie, red eye)
- Entropion
- Skin lesions
- Nasal lesions
- Mouth lesions
- Discharge (ie, catarrhal, mucous, membranous)
- Slit lamp examination
- Eye lids
- 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
- Eye lids
Causes
Various etiologic factors (eg, infection, vaccination, drugs, systemic diseases, physical agents, food) have been implicated as causes of SJS. Drugs most commonly are blamed. Reports have linked SJS to the use of drugs, rather than to other etiologic factors. Antibiotics are the most common cause of SJS, followed by analgesics, cough and cold medication, nonsteroidal anti-inflammatory drugs (NSAIDs), psychoepileptics, and antigout drugs. Other drugs also can be involved in the pathogenesis of SJS.Caucasians with HLA-Bw44 appear to be more susceptible to develop SJS. A Japanese report has shown that individuals with the HLA-A*0206 allele were prone to develop SJS-related ocular complications.8 Moreover, it was shown that certain HLA alleles were associated with an increased probability of developing SJS upon exposure to specific drugs. For example, patients with HLA-A29, HLA-B12, and HLA-DR7 were frequently associated with sulfonamide-induced SJS. Similarly, HLA-A2 and HLA-B12 were often encountered in SJS-induced by NSAIDs, while the HLA-B*5801 allele was found to be associated with SJS incited by allopurinol.9
The HLA class II molecules have been examined in patients with ocular manifestations secondary to SJS and found that the HLA-DQB1*0601 allele was strongly associated with SJS with ocular disease.10 Nevertheless, whether the presence of those genes constitutes a predisposition to SJS or whether those genes are in linkage disequilibrium with more relevant adjacent genes is unknown.11
More on Stevens-Johnson Syndrome |
 Overview: Stevens-Johnson Syndrome |
| Differential Diagnoses & Workup: Stevens-Johnson Syndrome |
| Treatment & Medication: Stevens-Johnson Syndrome |
| Follow-up: Stevens-Johnson Syndrome |
| Multimedia: Stevens-Johnson Syndrome |
| References |
| Next Page » |
References
Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol. Nov 1997;24(11):726-9. [Medline].
Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. Aug 2003;139(8):1051-9. [Medline].
Assier-Bonnet H, Aractingi S, Cadranel J, Wechsler J, Mayaud C, Saiag P. Stevens-Johnson syndrome induced by cyclophosphamide: report of two cases. Br J Dermatol. Nov 1996;135(5):864-6. [Medline].
De Rojas MV, Dart JK, Saw VP. The natural history of Stevens Johnson syndrome: patterns of chronic ocular disease and the role of systemic immunosuppressive therapy. Br J Ophthalmol. Aug 2007;91(8):1048-53. [Medline].
Foster CS, Fong LP, Azar D, Kenyon KR. Episodic conjunctival inflammation after Stevens-Johnson syndrome. Ophthalmology. Apr 1988;95(4):453-62. [Medline].
French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int. Mar 2006;55(1):9-16. [Medline].
French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol. Apr 2006;6(4):543-9. [Medline].
Hynes AY, Kafkala C, Daoud YJ, Foster CS. Controversy in the use of high-dose systemic steroids in the acute care of patients with Stevens-Johnson syndrome. Int Ophthalmol Clin. 2005;45(4):25-48. [Medline].
Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144-8. [Medline].
Khalili B, Bahna SL. Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol. Sep 2006;97(3):272-80; quiz 281-3, 320. [Medline].
Meth MJ, Sperber KE. Phenotypic diversity in delayed drug hypersensitivity: an immunologic explanation. Mt Sinai J Med. Sep 2006;73(5):769-76. [Medline].
Paquet P, Paquet F, Al Saleh W, Reper P, Vanderkelen A, Pierard GE. Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis. Am J Dermatopathol. Oct 2000;22(5):413-7. [Medline].
Patterson R, Dykewicz MS, Gonzalzles A, Grammer LC, Green D, Greenberger PA, et al. Erythema multiforme and Stevens-Johnson syndrome. Descriptive and therapeutic controversy. Chest. Aug 1990;98(2):331-6. [Medline].
Power WJ, Ghoraishi M, Merayo-Lloves J, Neves RA, Foster CS. Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology. Nov 1995;102(11):1669-76. [Medline].
Power WJ, Saidman SL, Zhang DS, Vamvakas EC, Merayo-Lloves JM, Kaufman AH, et al. HLA typing in patients with ocular manifestations of Stevens-Johnson syndrome. Ophthalmology. Sep 1996;103(9):1406-9. [Medline].
Hynes AY, Kafkala C, Daoud YJ, Foster CS. Controversy in the use of high-dose systemic steroids in the acute care of patients with Stevens-Johnson syndrome. Int Ophthalmol Clin. 2005;45(4):25-48. [Medline].
Mittmann N, Chan B, Knowles S, Cosentino L, Shear N. Intravenous immunoglobulin use in patients with toxic epidermal necrolysis and Stevens-Johnson syndrome. Am J Clin Dermatol. 2006;7(6):359-68. [Medline].
Neuman M, Nicar M. Apoptosis in ibuprofen-induced Stevens-Johnson syndrome. Transl Res. May 2007;149(5):254-9. [Medline].
Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol. Dec 1990;23(6 Pt 1):1039-58. [Medline].
Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. Dec 14 1995;333(24):1600-7. [Medline].
Stur K, Karlhofer FM, Stingl G. Soluble FAS ligand: a discriminating feature between drug-induced skin eruptions and viral exanthemas. J Invest Dermatol. Apr 2007;127(4):802-7. [Medline].
Ueta M, Sotozono C, Tokunaga K, Yabe T, Kinoshita S. Strong association between HLA-A*0206 and Stevens-Johnson syndrome in the Japanese. Am J Ophthalmol. Feb 2007;143(2):367-8. [Medline].
Yip LW, Thong BY, Lim J, Tan AW, Wong HB, Handa S, et al. Ocular manifestations and complications of Stevens-Johnson syndrome and toxic epidermal necrolysis: an Asian series. Allergy. May 2007;62(5):527-31. [Medline].
Yip LW, Thong BY, Tan AW, Khin LW, Chng HH, Heng WJ. High-dose intravenous immunoglobulin in the treatment of toxic epidermal necrolysis: a study of ocular benefits. Eye. Aug 2005;19(8):846-53. [Medline].
Further Reading
Keywords
SJS, toxic epidermal necrolysis, TEN, erythema multiforme, EM, erythema multiforme minor, von Hebra, erythema multiforme major, EMM
