STEVENS-JOHNSON SYNDROME

TOXIC EPIDERMAL NECROLYSIS

Jintana Chataroopwijit
23 September 2016
INTRODUCTION
➤ Severe cutaneous adverse reaction (SCAR)
➤ Immune-complex-mediated hypersensitivity complex
CLASSIFICATION
Body surface area detachment

1. Steven-Johnson syndrome : less than 10%

2. Overlapping Steven-Johnson syndrome/toxic epidermal necrolysis

3. Toxic epidermal necrolysis : more than 30%

EPIDERMIOLGY
➤ Steven-Johnson syndrome : 1-6 cases per million per year
➤ Toxic epidermal necrolysis : 1-2 cases per million per year
➤ Primarily male, AIDS patients

Autoimmunity Review 7 (2008) 598-608

INCIDENCE
ETIOLOGY
➤ Drug-induced
➤ Infectious
➤ Malignancy related
➤ Idiopathic

International Journal of Pharmacology Reasearch volume4 Issue4 (2014

ETIOLOGY : DRUG-INDUCED

Autoimmunity Review 7 (2008) 598-608

Alden
score
ETIOLOGY : INFECTIOUS

➤ Group A beta-hemolytic
➤ Herpes simplex virus streptococci
➤ AIDS ➤ Diphteria
➤ Coxsackie viral infection ➤ Brucellosis
➤ Influenza ➤ Lymphogranuloma venereum
➤ Hepatitis ➤ Mycobacteria
➤ Mumps ➤ Mycoplasma pneumoniae
➤ Epstein-Barr virus ➤ Rickettsial infections
➤ Enteroviruses ➤ Tularemia
➤ Typhoid

International Journal of Pharmacology Reasearch volume4 Issue4 (2014)

GENETIC SUSCEPTIBILITY

J Allergy Clin Immonol (2012) vol.136 no.2

GENETIC SUSCEPTIBILITY

J Allergy Clin Immonol (2012) vol.136 no.2

ETIOLOGY
➤ Malignancy related
➤ Photo-induced
➤ Post vaccination
➤ Idiopathic

Autoimmunity Review 7 (2008) 598-608

PATHOGENESIS
➤ Not fully understood
➤ Immune-mediated

Autoimmunity Review 7 (2008) 598-608

IMMUNOHISTOCHEMICAL CHARACTERISTICS
➤ Detection of activated T cell in lesion skin
➤ Predominance of CD4+ T cell in dermis and CD8+ in
epidermis

Autoimmunity Review 7 (2008) 598-608

HISTOLOGY OF DISEASE
PATHOGENESIS
J Allergy Clin Immonol (2012) vol.136 no.2
IMMUNOPATHOLOGY
➤ Two pathways leading to apoptosis cell death
➤ Ligation of Fas and FasL
➤ Release of Perforin and GranzymeB

Autoimmunity Review 7 (2008) 598-608

FAS/FAS LIGAND

➤ Fas
➤ Skin homeostasis
➤ Expression in normal keratinocyte at basal membrane
and first suprabasal cell layer
➤ In TEN : stain positive for FasL in perivascular and junctional
dermis in skin-infiltrating lymphocyte
➤ Ligation of Fas on keratinocyte by FasL on T cell -->
keratinocyte apoptosis

Autoimmunity Review 7 (2008) 598-608

FAS/FAS LIGAND
➤ Jurket cell
➤ Express high level of Fas
➤ Highly sensitive to Fas-induced apoptosis

Autoimmunity Review 7 (2008) 598-608

FAS/FAS LIGAND
➤ Soluble FasL (sFasL)
➤ Proteolytic processing membrane-bound form of FasL
➤ Level increasing in early but return to baseline levels
after progression creases
➤ Not specific for SJS/TEN but also in other drug-induced
cutaneous eruption, some inflammatory skin disease and
several autoimmune disease
➤ Unclear role

Autoimmunity Review 7 (2008) 598-608

FAS/FAS LIGAND

➤ Sera from TEN patients can induce apoptosis in normal

human keratinocytes and could be almost completely
inhibited by antiFasL mAb
➤ IVIG : blocking Fas activity

Autoimmunity Review 7 (2008) 598-608

PERFORIN/GRANZYME B
➤ Blister fluid in TEN
➤ CD8+ lymphocyte
➤ Markers of NK cells or cytotoxic T
➤ Able to lyse autologous keratinocyte in the presence of
causative drug

Autoimmunity Review 7 (2008) 598-608

PERFORIN/GRANZYME B
➤ Upregulation of MHC class I and induced MHC class II
expression

➤ Elevation CD8+ lymphocyte in PBMC and declined to below

control levels after systemic high dose conventional treatment

➤ Elevation of mRNA expression of perforin and granzyme B in

PBMC : severity of disease

Autoimmunity Review 7 (2008) 598-608

PERFORIN/GRANZYME B
➤ Drug-specific CTL
➤ Incresed expression of Perforin and Granzyme B on
epidermal CD8 T cell
➤ Induced an influx of CD4+ T cell into epidermis
➤ Keratinocyte apoptosis

Autoimmunity Review 7 (2008) 598-608

CYTOKINE DYSREGULATION
➤ Specimen from biopsy : express elevated levels of IFN-
gamma, TNF-alpha, IL-5, IL-6, IL-10 and IL-13

➤ Blister fluid : high concentration of IFN-gamma, TNF-alpha,

IL-6, IL-13 and IL-18(induce IFN-gamma)

Autoimmunity Review 7 (2008) 598-608

CYTOKINE DYSREGULATION
➤ IFN-gamma, TNF-alpha and IL-1beta along with IL-15 can
enhance surface expression of FasL on human keratinocyte

➤ Upregulation adhesion molecules --> recruitment of

lymphocyte to the skin

➤ Elabolation of type I cytokine profile ( IFN-gamma and TNF-

alpha --> major trigger keratinocyte apoptosis

Autoimmunity Review 7 (2008) 598-608

CLINICAL CHARACTERISTICS
➤ Influenza-like symptoms : 1-14 days
➤ Fever
➤ Cough
➤ Myalgias
➤ Arthralgias
➤ Malaise

Autoimmunity Review 7 (2008) 598-608

CLINICAL CHARACTERISTICS : SKIN LESION
➤ Flat, irregular, atypical target lesions or diffuse purpuric
macules with frequently necrotic center
➤ Mostly trunk and face, also neck and proximal extremities
➤ Positive Nickolsky sign
➤ Reepithelialization usually begins after a few days and
complete within 2-3 weeks

Autoimmunity Review 7 (2008) 598-608

CLINICAL MANIFESTRATION
SIMILARITIES IN CLINICAL PRESENTATION

Journal of Rare Disease 2010 , 5:39

International Journal of Pharmacology Reasearch volume4 Issue4 (2014)
CLINICAL CHARACTERISTICS
➤ Erythematous, painful erosion : Buccal mucosa, ocular and
genital mucosa
➤ Ocular involvement
➤ Acute conjunctivitis
➤ Eyelid edema and crusting to conjunctival memebrane or
pseudomembrane
➤ Cornea erosions
➤ Cicratizing symblepharon
➤ Conjunctival fornix foreshortening
➤ Corneal ulcer
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TREATMENT
FOUNDAMENTAL INTERDISCIPLINARY TREATMENT

Autoimmunity Review 7 (2008) 598-608

DRUG THERAPY
➤ Intravenous immunoglobulin
➤ Anti-Fas potential of pooled human intravenous
immunoglobulin
➤ Suggested dose : more than 2 g/kg
➤ One study showed that each 1 g/kg increase in IVIG = 4.2
fold in TEN patient survival

Harr and French Ophanet Journal of Rare Diseases 2010, 5:39

Harr and French Ophanet Journal of Rare Diseases 2010, 5:39
Harr and French Ophanet Journal of Rare Diseases 2010, 5:39
Harr and French Ophanet Journal of Rare Diseases 2010, 5:39
DRUG THERAPY
➤ Systemic steriod : controversy
➤ Thalidomide (anti TNF alpha) : higher mortality
➤ TNF antagonist : infliximab, etanercept
➤ Ciclosporin (CsA) : may be useful
➤ Cyclophosphamide (CPP)
➤ Plasmapheresis/plasma exchange

Harr and French Ophanet Journal of Rare Diseases 2010, 5:39

ALLERGOLOGICAL TESTING
➤ Detailed drug history
➤ Patch testing : low sensitivity
➤ Lymphocyte transformation test (LTT) : very low sensitivity
➤ Up regulation of CD69 on T-lymphocytes two days after
lymphocyte stimulation in vitro

Autoimmunity Review 7 (2008) 598-608

MORTALITY
MORTALITY