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
- Etiology
- 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)
- Etiology
- 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
- Widespread blisters predominantly on trunk and face, erythematous or pruritic macules, and one or more mucous membrane erosions
General Epidemiology
- Most anticonvulsant-induced SJS occurs in the first 60 days of use
- Genetic Risk Factors
- HLA-B1502
- HLA-B5801
- HLA-B44
- HLA-A29
- HLA-B12
- HLA-DR7
- HLA-A2
- 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
- xxxx
- xxxx
- xxxx
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
- Stevens-Johnson Syndrome (SJS): defined as total body surface area detachment <10%
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
- Dysphagia/Odynophagia: due to esophageal mucosal involvement
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]