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-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]])
  • Phenobarbital (see Phenobarbital, [[Phenobarbital]])
  • Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
  • Propylthiouracil (PTU) (see Propylthiouracil, [[Propylthiouracil]])
  • Sulfonamides (see Sulfonamides, [[Sulfonamides]])
  • 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

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]