Post on 15-Apr-2017
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
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
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 ulcerAutoimmunity Review 7 (2008) 598-608
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