stevens johnson syndrome & toxic epidermal necrolysis

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


Alden score

ETIOLOGY : INFECTIOUS

International Journal of Pharmacology Reasearch volume4 Issue4 (2014)

➤ Herpes simplex virus ➤ AIDS ➤ Coxsackie viral infection ➤ Influenza ➤ Hepatitis ➤ Mumps ➤ Epstein-Barr virus ➤ Enteroviruses

➤ Group A beta-hemolytic streptococci

➤ Diphteria ➤ Brucellosis ➤ Lymphogranuloma venereum ➤ Mycobacteria ➤ Mycoplasma pneumoniae ➤ Rickettsial infections ➤ Tularemia ➤ Typhoid

GENETIC SUSCEPTIBILITY

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

ETIOLOGY

➤ Malignancy related

➤ Photo-induced

➤ Post vaccination

➤ Idiopathic


PATHOGENESIS

➤ Not fully understood

➤ Immune-mediated


IMMUNOHISTOCHEMICAL CHARACTERISTICS

➤ Detection of activated T cell in lesion skin

➤ Predominance of CD4+ T cell in dermis and CD8+ in epidermis


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


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


FAS/FAS LIGAND

➤ Jurket cell

➤ Express high level of Fas

➤ Highly sensitive to Fas-induced apoptosis


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


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


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


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


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


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)


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


CLINICAL CHARACTERISTICS

➤ Influenza-like symptoms : 1-14 days

➤ Fever

➤ Cough

➤ Myalgias

➤ Arthralgias

➤ Malaise


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


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 ulcerAutoimmunity Review 7 (2008) 598-608

TREATMENT

FOUNDAMENTAL INTERDISCIPLINARY TREATMENT


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

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


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


MORTALITY

stevens johnson syndrome & toxic epidermal necrolysis

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