AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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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

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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

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

DIFFERENTIALS

Section 4 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Erythema multiforme
Staphylococcal scalded skin syndrome
Irradiation
Trauma
Progressive systemic sclerosis (scleroderma)
Erythroderma ichthyosiform congenita
Porphyria cutanea tarda
Epidermolysis bullosa acquisita
Linear immunoglobulin A bullous disease
Paraneoplastic pemphigus
Bullous systemic lupus erythematosus
Corynebacterium diphtheriae conjunctivitis
Sebaceous cell carcinoma
Adenoviral conjunctivitis
Intraepithelial epithelioma

WORKUP

Section 5 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Serum levels of TNF-alpha, soluble interleukin 2-receptor, interleukin 6, and C reactive protein are typically elevated in patients with SJS; however, none of these serologic tests is used routinely in diagnosing and managing SJS.

Procedures

• Skin biopsy is the only diagnostically helpful laboratory study.

Histologic Findings

Minimal dermal inflammatory cell infiltrate and full-thickness necrosis of epidermis are typical histopathologic findings in patients with SJS. The epidermal-dermal junction shows changes, ranging from vacuolar alteration to subepidermal blisters. The dermal infiltrate is superficial and mostly perivascular. Keratinocytes undergo apoptosis.

In the dermis, CD4⁺ T lymphocytes predominate, whereas in the epidermis, the T cells are predominantly CD8⁺. The dermoepidermal junction and epidermis is infiltrated mostly by CD8⁺ T lymphocytes. Complement 3 component and immunoglobulin G (IgG) deposits at the dermoepidermal junction and around small dermal vessels were interpreted as the result of a nonspecific exudative phenomenon. The activated state is underlined by HLA-DR expression on keratinocytes, similar to other skin inflammatory disorders.

CD8⁺ T cells that recognize major histocompatibility complex I (MHC-I) modified by an antigen may produce skin lesions of SJS, or they may be produced by T cells that recognize an antigen that is restricted by MHC-I.

Conjunctival biopsies from patients with active ocular disease show subepithelial plasma cells and lymphocyte infiltration. Lymphocytes also are present around vessel walls. The predominant infiltrating lymphocyte is the helper T cell.

Immunohistology of the conjunctiva reveals numerous HLA-DR positive cells in the substantia propria, vessel walls, and epithelium. In the epithelium, HLA-DR is presented by Langerhans cells, macrophages, and activated T cells.

Immunoreactant deposition in vessel walls, comprised of immunoglobulin and complement components, is another prominent feature.

On transmission electron microscopy, the conjunctivae of patients with episodic conjunctival inflammation revealed squamous epithelial metaplasia, vascular basement membrane zone disruption, reduplication, and thickening.

TREATMENT

Section 6 of 11  

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Medical Care

• Supportive systemic therapy: Management of patients with SJS is usually provided in ICUs or burn centers. No specific treatment of SJS exists; therefore, most patients are treated symptomatically. In principal, the symptomatic treatment of patients with SJS does not differ from the treatment of patients with extensive burns.
• • Fluid management is provided by macromolecules and saline solutions during the first 24 hours. Phosphate salts are necessary in the presence of hypophosphatemia. The amount of fluids required in patients with SJS is usually less than in those patients with burns covering the same body surface area.
  • After the second day of hospitalization, oral intake of fluids provided by nasogastric tube is often begun, so that intravenous fluids can be tapered progressively and discontinued, usually in 2 weeks.
  • Massive parenteral nutrition is necessary as soon as possible to replace the protein loss and to promote healing of cutaneous lesions.
  • Intravenous insulin therapy may be required because of impaired glycoregulation.
  • Patients with SJS are at a high risk of infection. Sterile handling and/or reverse-isolation nursing techniques are essential to decrease the risk of nosocomial infection.
  • Cultures of blood, catheters, gastric tubes, and urinary tubes must be performed regularly.
  • Because of the association between SJS and sulfonamides, avoid the use of silver sulfadiazine, which is commonly used in burn units; instead, use another antiseptic, such as 0.5% silver nitrate or 0.05% chlorhexidine, to paint and bathe the affected skin areas.
  • Prophylactic systemic antibiotics are not recommended.
  • The diagnosis of sepsis is difficult. Carefully consider the decision to administer systemic antibiotics. The first signs of infection are an increase in the number of bacteria cultured from the skin, a sudden drop in fever, and deterioration of the patient's condition, indicating the need for antibiotic therapy. The choice of antibiotic usually is based on the bacteria present on the skin. Because of impaired pharmacokinetics, similar to that present in burn patients, the administration of high doses may be required to reach therapeutic levels. Monitoring the serum levels is necessary to adjust the dosage.
  • Environmental temperature raised to 30-32°C reduces caloric loss through the skin. Fluidized air beds are recommended if a large portion of the skin on the patient's backside is involved. Heat shields and infrared lamps are used to help reduce heat loss.
  • Anticoagulation with heparin for the duration of hospitalization is recommended. Antacids reduce the incidence of gastric bleeding.
  • Pulmonary care includes aerosols, bronchial aspiration, and physical therapy. Tranquilizers are used to the extent limited by respiratory status.
  • Several skin care approaches have been described. Extensive debridement of nonviable epidermis, followed by immediate cover with biologic dressings, such as porcine cutaneous xenografts, cryopreserved cutaneous allografts, and amnion- or collagen-based skin substitutes, are among the recommended treatments. Leaving the involved epidermis that has not yet peeled off in place and using biologic dressings only on raw dermis also has been recommended. Skin allotransplantation reduces pain, minimizes fluid loss, improves heat control, and prevents bacterial infection. Hyperbaric oxygen also can improve healing.
• Immunomodulatory therapy: SJS is a rare disorder with relatively high mortality and morbidity rates. To date, because of a lack of consensus on the proposed therapeutic modalities, intensive supportive management and withdrawal of the offending drug remain the criterion standard. For any intervention, a prospective randomized controlled trial would be the most appropriate step to validate its use. However, a large number of patients are required to reach statistical significance. Furthermore, for ethical reasons, withdrawal of a potentially life-saving therapy for the sake of randomization with a placebo control is not possible.
• • Several therapeutic modalities have been advocated for the treatment of SJS based on the current, yet incomplete, understanding of its pathogenetic mechanisms. Plasmapheresis, immunosuppressive therapy, and intravenous immunoglobulin (IVIg) have been used with variably successful results.
  • The safety of systemic corticosteroids in the treatment of SJS is an issue that has been raised and is based on a few case series; in those reports, systemic corticosteroids were administered too late in the course of the disease, in inappropriately low doses, and for a very long duration that actually impaired the healing process and increased the risk of sepsis.  The currently advocated approach for corticosteroid use suggests the early use of short-term (4-7 d), high-dose intravenous corticosteroids.¹²
  • The role of other immunosuppressive therapy, that is, cyclosporine, azathioprine, or cyclophosphamide, in the acute phase is less popular, particularly since such medication typically takes weeks to begin to influence immunological reactions. Cyclophosphamide has been reported to be the culprit drug that induced SJS in one instance.¹³ Nevertheless, the role of cyclosporine in the treatment of the acute phase of SJS has been revisited, and, indeed, it showed encouraging results.⁵ Also, immunosuppressive therapy may play a pivotal role in the management of the chronic ocular surface inflammation that can take place later on in selected cases. 
  • The rational for the use of IVIg is the most appealing. Based on in vitro and clinical data, IVIg can block the Fas receptors on the surface of the keratinocytes, thus interfering with the Fas-Fas ligand mediated apoptosis.¹⁴ Encouraging results were reported when IVIg was used in high doses very early in the course of the disease and for a short period. Unfortunately, there is no consensus with regard to either the dose or the duration of treatment with IVIg.³
  • Interestingly, few studies have addressed the effect of systemic steroids or IVIg on either the development or the outcome of ocular manifestations in SJS and TEN. Neither treatment appeared to have an effect on the ocular outcome in patients in two reports.^{15, 1}

Surgical Care

• Treatment of acute ocular manifestations
• • Treatment of acute ocular manifestations usually begins with aggressive lubrication of the ocular surface.
  • As inflammation and cicatricial changes ensue, most ophthalmologists use topical steroids, antibiotics, and symblepharon lysis.
  • In case of exposure keratopathy, tarsorrhaphy may be required.
  • Maintenance of ocular integrity can be achieved through the use of amniotic membrane grafting, adhesive glues, lamellar grafts, and penetrating keratoplasty, either in the acute phase or in subsequent, follow-up care.
  • Visual rehabilitation in patients with visual impairment can be considered once the eye has been quiet for at least 3 months.
• Treatment of chronic ocular manifestations
• • In the case of mild chronic superficial keratopathy, long-term lubrication may be sufficient. In addition to lubrication, some patients may require a cosmetically acceptable long-term lateral tarsorrhaphy. The visual rehabilitation in patients with severe ocular involvement, resulting in profound dry eye syndrome with posterior lid margin keratinization, limbal stem cell deficiency, persistent epithelial defects with subsequent corneal neovascularization, and frank corneal opacity with surface conjunctivalization and keratinization, is difficult and often frustrating for both the patient and the physician. A close, usually long-term, relationship between the patient and the physician needs to be established to achieve the best possible result.
  • The removal of keratinized plaques from the posterior lid margins, along with mucous membrane grafting and/or amniotic membrane grafting, is usually the first step and one of the most important determining factors in the future success of corneal surgeries. Preferably, a skilled oculoplastic surgeon with specific experience on patients with SJS should perform this procedure.
• Subsequently, limbal stem cell transplantation and amniotic membrane grafting with superficial keratectomy removing conjunctivalized or keratinized ocular surface can follow. Patients with persistent corneal opacity require lamellar or penetrating keratoplasty in the next step, but each exposure to alloantigenic material increases the odds of tissue rejection. Therefore, the author’s advice is to strive for major, if not perfect, resurrection of the useful vision, rather than perform allografts of both eyes and keratoplasties.
• To preserve corneal clarity after the visual reconstruction, the long-term use of gas permeable scleral contact lenses may be necessary to protect the ocular surface. Long-term management frequently involves the treatment of trichitic lashes and/or eyelid margin repair for distichiasis or entropion. If the ocular surface repeatedly fails to heal upon multiple surgical interventions, keratoprosthesis may be considered as a last resort.

MEDICATION

Section 7 of 11  

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The goal of pharmacotherapy is to reduce morbidity and to prevent complications. For persistent or recurrent ocular inflammation, patients may benefit from short-term systemic corticosteroids and/or long-term immunosuppressive therapy, which may reduce severity of conjunctivitis and improve prognosis quod visum by reducing damage to ocular surface.

Drug Category: Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Drug Category: Immunosuppressants

Inhibit key factors of the immune system, reducing overall immune activity.

Drug Category: Immune globulins

These agents are used to improve clinical and immunologic aspects of the disease. They may decrease autoantibody production, and they may increase solubilization and removal of immune complexes.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
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Further Outpatient Care

• Medications and status of the disorder require regular monitoring.

Deterrence/Prevention

• Early recognition and avoidance of possible offending agents may reduce the incidence and/or severity of SJS.

Complications

• Ocular complications of SJS include the following:
• • Chronic cicatrizing conjunctivitis
  • Corneal epithelial defects
  • Corneal stromal ulcers
  • Corneal perforation
  • Endophthalmitis

Prognosis

• Of the patients with SJS, 27-50% progress to severe ocular disease.

Patient Education

• Educate the patient on the agents that might be responsible for this disorder.
• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Life-Threatening Skin Rashes.

MISCELLANEOUS

Section 9 of 11  

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• Miscellaneous
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Medical/Legal Pitfalls

• Failure to diagnose SJS in acute phase
• Failure to provide adequate supportive therapy in acute phase
• Failure to surgically treat chronic ocular problems

MULTIMEDIA

Section 10 of 11  

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• Miscellaneous
• Multimedia
• References

Media file 1:  A patient with severe eye involvement associated with Stevens-Johnson syndrome. Note corneal neovascularization and conjunctivalization of the ocular surface.
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Media type:  Photo

Media file 2:  Epithelial defect of the cornea with neovascularization and surface conjunctivalization.
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Media type:  Photo

REFERENCES

Section 11 of 11

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1. 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].
2. 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].
3. 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].
4. 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].
5. Foster CS, Fong LP, Azar D, Kenyon KR. Episodic conjunctival inflammation after Stevens-Johnson syndrome. Ophthalmology. Apr 1988;95(4):453-62. [Medline].
6. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int. Mar 2006;55(1):9-16. [Medline].
7. 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].
8. 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].
9. Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144-8. [Medline].
10. 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].
11. Meth MJ, Sperber KE. Phenotypic diversity in delayed drug hypersensitivity: an immunologic explanation. Mt Sinai J Med. Sep 2006;73(5):769-76. [Medline].
12. 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].
13. 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].
14. 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].
15. 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].
16. 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].
17. 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].
18. Neuman M, Nicar M. Apoptosis in ibuprofen-induced Stevens-Johnson syndrome. Transl Res. May 2007;149(5):254-9. [Medline].
19. 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].
20. 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].
21. 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].
22. 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].
23. 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].
24. 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].

Article Last Updated: Dec 18, 2007