Stevens johnson syndrome & toxic epidermal necrolysis Presented by Jintana Chataroopwijit, MD. September23, 2016

1. STEVENS-JOHNSON SYNDROME
TOXIC EPIDERMAL NECROLYSIS
Jintana Chataroopwijit
23 September 2016

2. INTRODUCTION
➤ Severe cutaneous adverse reaction (SCAR)
➤ Immune-complex-mediated hypersensitivity complex

3. 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%

5. 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

6. INCIDENCE

7. ETIOLOGY
➤ Drug-induced
➤ Infectious
➤ Malignancy related
➤ Idiopathic
International Journal of Pharmacology Reasearch volume4 Issue4 (2014

8. ETIOLOGY : DRUG-INDUCED
Autoimmunity Review 7 (2008) 598-608

11. Alden
score

13. 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

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

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

16. ETIOLOGY
➤ Malignancy related
➤ Photo-induced
➤ Post vaccination
➤ Idiopathic
Autoimmunity Review 7 (2008) 598-608

17. PATHOGENESIS
➤ Not fully understood
➤ Immune-mediated
Autoimmunity Review 7 (2008) 598-608

18. 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

19. HISTOLOGY OF DISEASE

20. PATHOGENESIS

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

22. IMMUNOPATHOLOGY
➤ Two pathways leading to apoptosis cell death
➤ Ligation of Fas and FasL
➤ Release of Perforin and GranzymeB
Autoimmunity Review 7 (2008) 598-608

23. 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

24. FAS/FAS LIGAND
➤ Jurket cell
➤ Express high level of Fas
➤ Highly sensitive to Fas-induced apoptosis
Autoimmunity Review 7 (2008) 598-608

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. CLINICAL CHARACTERISTICS
➤ Influenza-like symptoms : 1-14 days
➤ Fever
➤ Cough
➤ Myalgias
➤ Arthralgias
➤ Malaise
Autoimmunity Review 7 (2008) 598-608

33. 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

34. CLINICAL MANIFESTRATION

35. SIMILARITIES IN CLINICAL PRESENTATION
Journal of Rare Disease 2010 , 5:39
International Journal of Pharmacology Reasearch volume4 Issue4 (2014)

36. 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
Autoimmunity Review 7 (2008) 598-608

37. TREATMENT

38. FOUNDAMENTAL INTERDISCIPLINARY TREATMENT
Autoimmunity Review 7 (2008) 598-608

39. 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

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

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

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

43. 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

44. 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

45. MORTALITY

46. MORTALITY