Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Epidemiology

Historical Terminologic Controversy

1866: Erythema Multiform (EM) was first described by Ferdinand von Hebra
- Epidemiology: association with Herpes-Simplex Virus
- Clinical Features: acral (peripheral) skin lesion, consisting of target lesions, edematous papules, and/or plaques without mucosal involvement
1922: Stevens-Johnson Syndrome (SJS) was described a pediatric febrile mucocutaneous disorder with febrile erosive stomatitis, severe conjunctivitis, and disseminated cutaneous eruption
1948: first description of Toxic Epidermal Necrolysis (TEN)
1950: Thomas proposed the subclassification of EM
- Erythema Multiforme Minor: acute, self-limited condition with characteristic red papular skin lesions
- Erythema Multiforme Major: applied to patients who also displayed oral mucosal involvement
  - Note: this subset included patients with SJS (and some Dermatologists confusingly use this term and SJS interchangeably)
Current State of Understanding
- Strong association between Herpes-Simplex Virus and EM
- SJS is more commonly associated with exogenous agents (such as drugs)
- Studies of IL-13 and other cytokines suggest that SJS and TEN are related, while EM is a distinct disorder

Current Classification Schema (Based on 1993 Classification)

Erythema Multiforme Minor (see [[Erythema Multiforme]])
- Etiology
  - Typically due to Herpes-Simplex Virus
- Clinical
  - Typical targets or raised, edematous papules distributed acrally (peripherally)
  - Absence of mucosal involvement
Erythema Multiforme Major (see [[Erythema Multiforme]])
- Etiology
  - Typically due to Herpes-Simplex Virus, Mycoplasma Pneumoniae, and drugs
- Clinical
  - Typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes
  - Epidermal detachment involves <10% of total body surface area
  - Commonly involves mucosal membranes (oral, nasal, ocular, genital)
  - Hemorrhagic crusting of lips (also may be seen in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis, Herpes-Simplex Virus, Pemphigus Vulgaris, and Paraneoplastic Pemphigus)
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
- Widespread blisters predominantly on trunk and face, erythematous or pruritic macules, and one or more mucous membrane erosions
  - Stevens-Johnson Syndrome: epidermal detachment is <10% of body surface area
  - Toxic Epidermal Necrolysis: epidermal detachment is >30% of body surface area

General Epidemiology

Most anticonvulsant-induced SJS occurs in the first 60 days of use
Genetic Risk Factors
- HLA-B1502
- HLA-B5801
- HLA-B44
- HLA-B5801
- HLA-A0206
- HLA-DQB10601

Definitions

Stevens-Johnson Syndrome (SJS): defined as total body surface area detachment <10%
Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) Overlap: defined as total body surface area detachment 10-30%
Toxic Epidermal Neocrolysis (TEN): defined as total body surface area detachment >30%

Etiology

Relative Incidence of Various Etiologies [MEDLINE]

Allopurinol (see Allopurinol, [[Allopurinol]]): 20% of cases
Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]]): 16% of cases
Carbamazepine (Tegretol) (see Carbamazepine, [[Carbamazepine]]): 8% of cases
Sulfamethoxazole-Trimethoprim (Bactrim, Septra) (see Sulfamethoxazole-Trimethoprim, [[Sulfamethoxazole-Trimethoprim]]): 6% of cases
Ibuprofen (Advil) (see Ibuprofen, [[Ibuprofen]]): 5% of cases
Amoxacillin (xxx) (see Amoxacillin, [[Amoxacillin]]): 2% of cases
Atenolol (Tenormin) (see Atenolol, [[Atenolol]]): 2% of cases
Cephalexin (xxx) (see Cephalexin, [[Cephalexin]]): 2% of cases
Ceftriaxone (Rocephin) (see Ceftriaxone, [[Ceftriaxone]]): 2% of cases
Ciprofloxacin (Cipro) (see Ciprofloxacin, [[Ciprofloxacin]]): 2% of cases
Clarithromycin (Biaxin) (see Clarithromycin, [[Clarithromycin]]): 2% of cases
Diltiazem (Cardizem) (see Diltiazem, [[Diltiazem]]): 2% of cases
Doxycycline (see Doxycycline, [[Doxycycline]]): 2% of cases
Lamotrigine (Lamictal) (see Lamotrigine, [[Lamotrigine]]): 2% of cases
Terbinafine (see Terbinafine, [[Terbinafine]]): 2% of cases
Piperacillin-Tazobactam (Zosyn) (see Piperacillin-Tazobactam, [[Piperacillin-Tazobactam]]): 2% of cases
Vancomycin (see Vancomycin, [[Vancomycin]]): 2% of cases
Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae, [[Mycoplasma Pneumoniae]]): 2% of cases
Unknown: 25% of cases

Drugs

Allopurinol (see Allopurinol, [[Allopurinol]]): presence of HLA B5801 increases risk
Anti-TNF Therapy (see Anti-TNF Therapy, [[Anti-TNF Therapy]]): infliximab, etanercept, adalimumab
Carbamazepine (Tegretol) (see Carbamazepine, [[Carbamazepine]])
Cephalosporins
- Cephalexin (xxx) (see Cephalexin, [[Cephalexin]])
- Ceftriaxone (Rocephin) (see Ceftriaxone, [[Ceftriaxone]]):
Ciprofloxacin (Cipro) (see Ciprofloxacin, [[Ciprofloxacin]])
Clarithromycin (Biaxin) (see Clarithromycin, [[Clarithromycin]])
Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]]): case reports
Diltiazem (Cardizem) (see Diltiazem, [[Diltiazem]])
Doxycycline (see Doxycycline, [[Doxycycline]])
Indinavir (Crixivan) (see Indinavir, [[Indinavir]])
Lamotrigine (Lamictal) (see Lamotrigine, [[Lamotrigine]])
Lenalidomide (Revlimid) (see Lenalidomide, [[Lenalidomide]])
Mirtazapine (Remeron) (see Mirtazapine, [[Mirtazapine]])
Modafinil (Provigil) (see Modafinil, [[Modafinil]])
Nevirapine (Viramune) (see Nevirapine, [[Nevirapine]])
Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]]): specific agents have been implicated
- Ibuprofen (xxx) (see Ibuprofen, [[Ibuprofen]])
- Enolic Acid (Oxicam) Derivatives
  - Droxicam
  - Lornoxicam
  - Meloxicam (Mobic) (see Meloxicam, [[Meloxicam]])
  - Phenylbutazone (see Phenylbutazone, [[Phenylbutazone]])
  - Piroxicam (Feldene) (see Piroxicam, [[Piroxicam]])
  - Tenoxicam
Oxcarbazepine (Trileptal) (see Oxcarbazepine, [[Oxcarbazepine]])
Penicillins (see Penicillins, [[Penicillins]])
- Piperacillin-Tazobactam (Zosyn) (see Piperacillin-Tazobactam, [[Piperacillin-Tazobactam]])
Phenobarbital (see Phenobarbital, [[Phenobarbital]])
Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
Propylthiouracil (PTU) (see Propylthiouracil, [[Propylthiouracil]])
Sulfonamides (see Sulfonamides, [[Sulfonamides]])
- Sulfamethoxazole-Trimethoprim (Bactrim, Septra) (see Sulfamethoxazole-Trimethoprim, [[Sulfamethoxazole-Trimethoprim]])
Terbinafine (see Terbinafine, [[Terbinafine]])
Valproic Acid (Valproate) (see Valproic Acid, [[Valproic Acid]])
Vancomycin (see Vancomycin, [[Vancomycin]])
Varenicline (Chantix) (see Varenicline, [[Varenicline]])

Infection

AIDS (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
Brucellosis (see Brucellosis, [[Brucellosis]])
Coccidioidomycosis (see Coccidioidomycosis, [[Coccidioidomycosis]])
Coxsackie Virus (see Coxsackie Virus, [[Coxsackie Virus]])
Dermatophytosis
Diphtheria (see Diphtheria, [[Diphtheria]])
Enterovirus: association in children
Epstein-Barr Virus (EBV) (see [[Epstein-Barr Virus]]): association in children
Streptococcus Pyogenes (Group A Beta-Hemolytic Streptococcus) (see Streptococcus Pyogenes, [[Streptococcus Pyogenes]])
Hepatitis (see xxxx, [[]])
Herpes Simplex Virus (HSV) (see Herpes Simplex Virus, [[Herpes Simplex Virus]]): unclear association with SJS/TEN
Histoplasmosis (see Histoplasmosis, [[Histoplasmosis]])
Influenza Virus (see Influenza Virus, [[Influenza Virus]])
Lymphogranuloma Venereum (LGV) (see xxxx, [[]])
Malaria (see Malaria, [[Malaria]])
Mumps Virus (see Mumps Virus, [[Mumps Virus]])
Mycobacteria (see xxxx, [[]])
Mycoplasma Pneumoniae (see Mycoplasma Pneumoniae, [[Mycoplasma Pneumoniae]])
Rickettsia (see xxxx, [[]])
Trichomoniasis (see Trichomoniasis, [[Trichomoniasis]])
Tularemia (see Tularemia, [[Tularemia]])
Typhoid (see Typhoid, [[Typhoid]])

Malignancy

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Idiopathic Stevens-Johnson Syndrome-Toxic Epidermal Necrolysis

Epidemiology: Accounts for 10-20% of cases

Physiology

Epidermal necrosis (in absence of substantial dermal inflammation) -> blisters and epidermal detachment

Diagnosis

Skin Biopsy: may aid in early diagnosis
- Minimal dermal inflammatory infiltrate and full-thickness epidermal necrosis

Clinical

Prodromal Syndrome

May last 1-14 days prior to onset of skin lesions
Clinical Features
- Fever/Chills
- Malaise
- Sore Throat
- Headache
- Vomiting
- Diarrhea
- Cough with Sputum
- Arthralgias

Dermatologic Manifestations

Painful (Non-Pruritic) Skin Lesions: occur abruptly and clusters last 2-4 wks
- Stevens-Johnson Syndrome (SJS): defined as total body surface area detachment <10%
  - Small blisters on atypical target lesions or on dusky or purpuric macules (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]]): rare areas of confluence
- Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) Overlap: defined as total body surface area detachment 10-30%
- Toxic Epidermal Neocrolysis (TEN): defined as total body surface area detachment >30%
  - Small blisters on atypical target lesions or on dusky or purpuric macules (see Vesicular-Bullous Skin Lesions, [[Vesicular-Bullous Skin Lesions]])
  - Confluent erythema
  - Lateral pressure -> outer layer of epidermis separates easily from basal layer
  - Large sheets of necrotic epidermis

Ocular Mucosal Involvement

Conjunctivitis
Dry Eye
Diplopia
Photophobia
Decreased Vision
Complications: 27-50% progress to severe ocular disease
- Chronic cicatrizing conjunctivitis
- Corneal epithelial defects
- Corneal stromal ulcers
- Corneal perforation
- Endophthalmitis

Gastrointestinal Manifestations

Poor prognostic sign
Clinical Features
- Dysphagia/Odynophagia: due to esophageal mucosal involvement
  - May result in esophageal strictures

Pulmonary Manifestations

Poor prognostic sign
Clinical Features
- Sore Throat: due to mucosal upper airway involvement

Urologic Manifestations

Dysuria: due to urethral mucosal involvement

Other Manifestations

Fever (85% of cases): seen in most cases of SJS and almost all cases of TEN
Leukopenia: seen in TEN

Treatment

Discontinue Drug necessary
Supportive Care: necessary
Intravenous Immunoglobulin (IVIG)
- Mechanism: blocks Fas receptors on the keratinocyte surface, interfering with Fas-Fas ligand mediated apoptosis
- Early trials suggested promise, but IVIG is unlikely to improve mortality
- Some trials have reported the use of prophylactic IVIG in patients with prior contrast-induced SJS/TEN
Corticosteroids
- Prednisone 1-2 mg/kg/day may be useful early in the course, but longer-term use may increase mortality
Cyclosporine-A: has been used in some cases

Prognosis

Predictors of Poor Prognosis
- Greater Extent of Epidermal Detachment
- Pulmonary Involvement
- Intestinal Involvement
- Oder Age
Mortality Rate from SJS: 10%
Mortality Rate from TEN: 30%

References

Stevens-Johnson Syndrome Induced by Sodium Valproate. Indian J Psychiatry. 2004 Jul-Sep; 46(3): 269–270
Stevens-Johnson syndrome induced by sodium valproate monotherapy. Int J Crit Illn Inj Sci. 2012 Jan-Apr; 2(1): 44–45
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].
Stevens-Johnson syndrome induced by cyclophosphamide: report of two cases. Br J Dermatol. Nov 1996;135(5):864-6
Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol. Feb 2004;50(2):286-8
Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. Jan 2008;58(1):33-40
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: An Analysis of Triggers and Implications for Improving Prevention. Am J Med. 2016 Apr 15. pii: S0002-9343(16)30350-3. doi: 10.1016/j.amjmed.2016.03.022 [MEDLINE]