Scratching the Surface: A Review of SJS/TEN

Size: px

Start display at page:

Download "Scratching the Surface: A Review of SJS/TEN"

Jeremy Greene
5 years ago
Views:

1 Scratching the Surface: A Review of SJS/TEN Sarah Smith, PharmD Pharmacy Grand Rounds 2018 November 27, MFMER slide 1

2 Toxic Epidermal Necrolysis Cutaneous Anthrax Stevens Johnson Syndrome Necrotizing Fasciitis Toxic Shock Syndrome Rocky Mountain Spotted Fever Meningococcemia Did you know there are 7 types of dermatological emergencies? 2018 MFMER slide 2

3 Objectives 1. Review the pathophysiology of Stevens Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) 2. Identify medications that may induce SJS/TEN 3. Discuss pharmacological interventions used to treat patients who present with SJS/TEN 2018 MFMER slide 3

4 Abbreviations SJS: Stevens Johnson syndrome TEN: Toxic epidermal necrolysis CBZ: carbamazepine APC: antigen presenting cell IVIG: intravenous immune globulin FasL: Fas ligand sfasl: soluble Fas ligand TNF α: Tumor necrosis factor alpha RCT: randomized control trial CTL: cytotoxic T lymphocytes SCARs: severe cutaneous adverse reactions 2018 MFMER slide 4

5 Patient Case 38 year old male PMH: epileptic seizures Developed high fever, sloughing of the epidermis, and clinical appearance of severe burn patient 2 weeks after starting a new antiepileptic medication 2018 MFMER slide 5

6 SJS/TEN Acute, life threatening hypersensitivity cutaneous reactions Characterized by full thickness epidermal necrosis Varying involvement of cutaneous, extracutaneous, and mucous membrane involvement Usatine RP, Sandy N. Dermatologic Emergencies, Jellinek. Am Fam Physician. 2010;82(7): Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): MFMER slide 6

7 Distinguishing SJS vs TEN >30% BSA 10% BSA 10 30% BSA SJS SJS/TEN overlap TEN Percentage of BSA affected Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): MFMER slide 7

8 Clinical Course of SJS/TEN Prodrome: malaise, rash, fever, cough, myalgia 1 4 weeks after drug exposure Epidermal detachment progresses, large denuded areas Extreme pain, massive fluid & protein loss, hypothermia days Signs begin in mucous membranes Skin lesions start to manifest, progress to large blisters Re epithelialization of the epidermis begins May take up to 3 weeks Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): MFMER slide 8

9 Clinical Presentation Extracutaneous Nonspecific: Malaise, rash, fever, pain, cough, headache, N/V Respiratory Large ulcerations and epithelial necrosis of bronchial epithelium, respiratory distress, pulmonary edema, progressive respiratory failure Gastrointestinal Diarrhea, nausea, malabsorption, colonic perforation, melena Renal Proteinuria, hematuria, microalbuminuria Valeyrie Allanore L, Roujeau J. Chapter 40. Epidermal necrolysis (Stevens Johnson syndrome and toxic epidermal necrolysis). In: Goldsmith LA, Katz SI, Gilchrest BA et al, eds. Fitzpatrick s Dermatology in General Medicine. 8 th ed. New York, NY: McGraw Hill; 2012 Harr T, French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome. Orphanet J Rare Dis. 2010;5(1):39. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Mockenhaupt M. The current understanding of Stevens Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6): MFMER slide 9

Clinical Presentation Cutaneous Initial Phase: Erythematous, dusky red, flat atypical target lesions with necrotic centers Lesions evenly distributed on face/trunk/proximal part of limbs Later phase:

10 Clinical Presentation Cutaneous Initial Phase: Erythematous, dusky red, flat atypical target lesions with necrotic centers Lesions evenly distributed on face/trunk/proximal part of limbs Later phase: Lesions coalesce and evolve into flaccid blisters Epidermal detachment + Nikolsky sign Gentle lateral pressure causes lesional, detachable epidermis Early Phase Blistering, peeling skin with epidermal detachment Flat, dusky red atypical target lesions Later Phase Adapted from JAMA 2017; 153 (12): 1344 Valeyrie Allanore L, Roujeau J. Chapter 40. Epidermal necrolysis (Stevens Johnson syndrome and toxic epidermal necrolysis). In: Goldsmith LA, Katz SI, Gilchrest BA et al, eds. Fitzpatrick s Dermatology in General Medicine. 8 th ed. New York, NY: McGraw Hill; 2012 Harr T, French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome. Orphanet J Rare Dis. 2010;5(1):39. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Mockenhaupt M. The current understanding of Stevens Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6): MFMER slide 10

Clinical Presentation Mucous membrane Ocular: Eyelid edema, redness, photophobia, discharge, lacrimation Buccal/Oral: Erosive, hemorrhagic lesions, grayish white pseudomembranes, crust on lips, nose

Buccal/Oral Adapted from JAMA 2017; 153 (12): 1344 Valeyrie Allanore L, Roujeau J. Chapter 40. Epidermal necrolysis (Stevens Johnson syndrome and toxic epidermal necrolysis).

11 Clinical Presentation Mucous membrane Ocular: Eyelid edema, redness, photophobia, discharge, lacrimation Buccal/Oral: Erosive, hemorrhagic lesions, grayish white pseudomembranes, crust on lips, nose involvement Genital Erosive hemorrhagic lesions, painful urination Ocular Redness, blisters, pain, and erosions of the lips and inside the mouth Redness, irritation, pain, and erosions of the eyelids Buccal/Oral Adapted from JAMA 2017; 153 (12): 1344 Valeyrie Allanore L, Roujeau J. Chapter 40. Epidermal necrolysis (Stevens Johnson syndrome and toxic epidermal necrolysis). In: Goldsmith LA, Katz SI, Gilchrest BA et al, eds. Fitzpatrick s Dermatology in General Medicine. 8 th ed. New York, NY: McGraw Hill; 2012 Harr T, French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome. Orphanet J Rare Dis. 2010;5(1):39. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Mockenhaupt M. The current understanding of Stevens Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6): MFMER slide 11

12 Epidemiology US incidence: cases per 1 million people per year 1,178 cases reported to the FDA in 2017 More common in women Female to male ratio of 1.5:1 Ward KE, Archambault R, Mersfelder TL. Severe adverse skin reactions to nonsteroidal anti inflammatory drugs: a review of the literature. Am J Health Syst Pharm. 2010; 67: Four severe adverse events and the leading suspect drugs. ISMP Medication Safety Alert! Acute Care. 2018: 23 (18) MFMER slide 12

13 Mortality Mortality estimates: SJS: % SJS/TEN overlap: 19.4% TEN: 15 50% SCORTEN criteria Severity of illness score to predict mortality for SJS/TEN Measure on days 1 & 3 of hospitalization Wang C W, Yang L Y, Chen C B, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): Hsu DY, Brieva J, Silverberg NB, Silverberg JI. Morbidity and Mortality of Stevens Johnson Syndrome and Toxic Epidermal Necrolysis in United States Adults. J Invest Dermatol. 2016;136(7): Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Guegan S, Bastuji Garin S, Poszepczynska Guigne E, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol. 2006; 126 (2): MFMER slide 13

14 SCORTEN criteria Age >40 years Malignancy BSA >10% Heart rate >120 bpm BUN >28 mg/dl Serum glucose >250 mg/dl Serum bicarbonate <20 mmol/l 1 point for each risk factor present # Risk Factors Predicted Mortality 0 1% 1 4% 2 12% 3 32% 4 62% 5 85% 6 95% 7 99% Guegan S, Bastuji Garin S, Poszepczynska Guigne E, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol. 2006; 126 (2): Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e MFMER slide 14

15 Patient Case 38 year old male PMH: epileptic seizures Developed high fever, sloughing of the epidermis, and clinical appearance of severe burn patient 2 weeks after starting a new antiepileptic medication 2018 MFMER slide 15

16 Patient Case 80% BSA involvement Lab values HR: 132 bpm BUN: 36 mg/dl Serum creatinine: 1.2 mg/dl Glucose: 186 mg/dl Bicarbonate: 28 mmol/l 2018 MFMER slide 16

17 How would you classify this patient? a) SJS b) SJS/TEN overlap c) TEN 2018 MFMER slide 17

18 How would you classify this patient? a) SJS b) SJS/TEN overlap c) TEN 2018 MFMER slide 18

19 Etiology Known causes: Drugs Most common 50% of SJS cases; 80 90% of TEN cases Vaccinations MMR, varicella, tetanus, influenza, hantavirus (HFRS) Sunlight exposure Pregnancy Harr T, French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome. Orphanet J Rare Dis. 2010;5(1):39. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Usatine RP, Sandy N. Dermatologic Emergencies, Jellinek. Am Fam Physician. 2010;82(7): MFMER slide 19

20 Etiology Known causes: Infectious agents Herpes virus, Mycoplasma pneumoniae, HIV, Hepatitis A Noninfectious conditions: Cancer, radiation, lupus erythematosus, collagen vascular disease Bone marrow/solid organ transplants Idiopathic Harr T, French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome. Orphanet J Rare Dis. 2010;5(1):39. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Usatine RP, Sandy N. Dermatologic Emergencies, Jellinek. Am Fam Physician. 2010;82(7): MFMER slide 20

21 Genetic Factors HLA B*15:02 Carbamazepine, lamotrigine, oxcarbazepine, & phenytoin related SJS/TEN Asian ancestry HLA B*58:01 Allopurinolrelated SJS/TEN Asian & Non Asian populations HLA A*31:01 Carbamazepinerelated SJS/TEN Japanese, Indian, & European ancestry Other possible associations: HLA B*15:08, HLA B*15:11, HLA B*15:18 & HLA B*51:01 Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): MFMER slide 21

22 SJS/TEN Inducing Medications Most Common Agents Allopurinol Carbamazepine Lamotrigine Nevirapine Oxicam NSAIDS Phenobarbital Phenytoin Sulfamethoxazole and other sulfur antibiotics Sulfasalazine Other Suspected Agents Antibiotics: Aminopencillins, Cephalosporins, Quinolones, Tetracyclines, Macrolides Valproicacid Oxcarbazepine Abacavir Diclofenac Zonisamide Lenalidomide Acetazolamide Ethambutol Mirtazapine Oseltamivir Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e153. Ruminski MA, Wisneski SS, Dugan SE. Stevens Johnson syndrome: what a pharmacist should know. US Pharm. 2013; 38(7): MFMER slide 22

23 Drug-Induced SJS/TEN Most often occurs within 4 28 days of 1 st exposure to suspect drug May also occur: Within hours upon rechallenge Up to 8 weeks post exposure ALDEN (ALgorithm of Drug causality for Epidermal Necrolysis) Assessment tool for drug causality in SJS/TEN Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e MFMER slide 23

24 Pathophysiology SJS/TEN characterized by: Apoptotic keratinocyte cell death in the epidermis Epidermal detachment and necrosis Exact pathogenesis unknown Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Ruminski MA, Wisneski SS, Dugan SE. Stevens Johnson syndrome: what a pharmacist should know. US Pharm. 2013; 38(7): MFMER slide 24

25 One Proposed Theory of Pathogenesis: CBZ + protein CBZ + protein APC APC Tcell release of cytokines CBZ + protein APC T cell Granulysin, sfasl, Perforin, Granzyme B CBZ = carbamazepine, APC = antigen presenting cell, sfasl = soluble Fas ligand Valeyrie Allanore L, Roujeau J. Chapter 40. Epidermal necrolysis (Stevens Johnson syndrome and toxic epidermal necrolysis). In: Goldsmith LA, Katz SI, Gilchrest BA et al, eds. Fitzpatrick s Dermatology in General Medicine. 8 th ed. New York, NY: McGraw Hill; 2012 Ruminski MA, Wisneski SS, Dugan SE. Stevens Johnson syndrome: what a pharmacist should know. US Pharm. 2013; 38(7): Chung WH, Hung SI, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12): MFMER slide 25

26 Complications Secondary skin infections Bloodstream infections Eye problems Persistent respiratory sequelae Permanent skin damage Abnormal bumps, coloring, possible scarring Hair loss, nail deformities Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): MFMER slide 26

27 Patient Case 38 year old male PMH: epileptic seizures Developed high fever, sloughing of the epidermis, and clinical appearance of severe burn patient 2 weeks after starting a new antiepileptic medication 2018 MFMER slide 27

28 Patient Case 80% BSA involvement Lab values HR: 132 bpm BUN: 36 mg/dl Glucose: 186 mg/dl Bicarbonate: 28 mmol/l 2018 MFMER slide 28

29 What medication most likely caused this patient s reaction? a) Lamotrigine b) Valproic acid c) Oxcarbazepine 2018 MFMER slide 29

30 What medication most likely caused this patient s reaction? a) Lamotrigine b) Valproic acid c) Oxcarbazepine 2018 MFMER slide 30

31 Treatment Approach No formal US Guidelines available Early drug withdrawal Transfer to burn ICU Supportive care Room temp C Consult specialties Dermatology Ophthalmology Urology Calculate SCORTEN Days 1 & 3 Consider adjuvant therapies Within h Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e153. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): MFMER slide 31

32 Supportive Care Pain Control Fluids Antibiotics No current guidelines PCAs may be difficult due to hand involvement Avoid morphine when able Aggressive fluid & electrolyte replacement Maintain urine output ml/kg/h Only if infection is present May lead to drug resistance Potential to worsen skin toxicity Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e153. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): MFMER slide 32

33 Supportive Care Eye Care Eye emollients Antiseptic eye drops Topical antibiotics Topical steroids Severe cases: amniotic membrane transplantation Wound Care Disinfecting mouthwashes (chlorhexidine) Mild ointments (white petrolatum) Avoid topical antiinfectives with a sulfa moiety Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e153. Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): MFMER slide 33

34 Treatment Consider adjuvant therapies Systemic corticosteroids IVIG Cyclosporine Infliximab Etanercept Plasmapheresis 2018 MFMER slide 34

35 Corticosteroids Proposed mechanism: Ability to modify inflammatory and immune responses 2018 MFMER slide 35

36 Corticosteroids Author & year Study type Number patients Halebian et al. Retrospective comparative trial Treatment 30 Hydrocortisone 240 1,000 mg over max 7 days Mortality with/without steroids 66% / 33% Other Kelemen et al. Retrospective 51 NR 50% / 3% Infection, hospitalization, & mortality reduced if <48 h steroids Kakourou et al. Retrospective 16 Methylprednisolone mg/kg/day 0% / 0% Shorter period of fever with steroids Forman et al. Retrospective 39 NR 3.6% / 21% complications Kardaun and Jonkman Retrospective 12 Dexamethasone 100 mg or 1.5 mg/kg x 3 days Yamane et al. Retrospective 117 Prednisolone mg/day Schneck et al. Retrospective multicenter Yang et al. Retrospective TEN SJS % / 3.6% / 16.6% 281 NR 17.6% / 27.8% No significant benefit to any treatment Methylprednisolone mg/kg/day 27% / 16.7% / 16% more likely to die with steroids Adapted from: Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): MFMER slide 36

37 IVIG Proposed mechanism: Ability to block Fas and subsequent FasL mediated apoptosis of keratinocytes Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): MFMER slide 37

38 IVIG Author & year Study type Number patients Bachot et al. Prospective open trial Treatment average total IVIG dose (g/kg) (3 patients) 2.0 (31 patients) Mortality with/without IVIG 32% / Other Metry et al. Retrospective % / Early treatment correlated with longer time to response Brown et al. Retrospective % / 28.6% Yeung et al. Prospective/ retrospective controls % / 10% Shorter time to cessation of progression and reepithelialization with IVIG Gravante et al. Retrospective % / 27% Stella et al. Retrospective % / 75% Yamane et al. Retrospective 117 Max 1.2 9% / 3% Schneck et al Retrospective % / 20.8% No significant benefit from any treatment Yang et al. Retrospective % / 22.8% Nonsignificant reductions in mortality, time of progression, and Adapted from: Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): MFMER slide 38

39 The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre Lee HY, Lim YL, Thirumoorthy T, and Pang SM. British Journal of Dermatology MFMER slide 39

40 Study Design Primary Endpoint Evaluate the risk of in hospital mortality Study Methods Single center, retrospective analysis 64 patients included from Lee HY, Lim YL, Thirumoorthy T, and Pang SM. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. British Journal of Dermatology ; 169: MFMER slide 40

41 Enrollment Inclusion Diagnosed with SJS/TEN overlap or TEN Treated with IVIG Exclusion Exclusion Criteria Diagnosed with SJS No progression of disease Primary treatment with corticosteroids Lee HY, Lim YL, Thirumoorthy T, and Pang SM. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. British Journal of Dermatology ; 169: MFMER slide 41

42 Clinical Characteristics Characteristic IVIG (n = 64) Sex male, n (%) 26 (41) Age (years) 57 ± 19 Ethnicity, n (%) Chinese 42 (66) Malay 18 (28) Indian 4 (6) SCORTEN overall 2.6 ± 1.2 Cumulative dose IVIG (g/kg) 2.4 ± 0.8 Daily dosage (g/kg/day) 0.6 ± 0.2 Duration of administration (days) 4.0 ± 1.3 Lee HY, Lim YL, Thirumoorthy T, and Pang SM. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. British Journal of Dermatology ; 169: MFMER slide 42

43 Results Primary Predicted mortality, n Observed mortality, n Standardized mortality (95% CI) n = ( ) Secondary Analyses Parameter Survivors (n = 44) Non survivors (n = 20) p value SCORTEN 2.2 ± ± 1.0 <0.001 Secondary Analyses Parameter Low dose IVIG <3 g/kg (n = 42) SCORTEN 2.6 ± ± 0.9 High dose IVIG 3 g/kg (n = 19) p value Observed mortality, n (%) 13 (31) 5 (26) 0.71 Lee HY, Lim YL, Thirumoorthy T, and Pang SM. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. British Journal of Dermatology ; 169: MFMER slide 43

44 Conclusions Limitations: retrospective design, varied dosing strategies Conclusions: IVIG does not confer a significant survival benefit Lee HY, Lim YL, Thirumoorthy T, and Pang SM. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. British Journal of Dermatology ; 169: MFMER slide 44

45 Cyclosporine Proposed mechanism: A calcineurin inhibitor with the ability to block the function of T cells Schneider JA, Cohen PR. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis: A Concise Review with a Comprehensive Summary of Therapeutic Interventions Emphasizing Supportive Measures. Adv Ther. 2017;34(6): Gerull R, Nelle M, Schaible T. Toxic epidermal necrolysis and Stevens Johnson syndrome: a review. Crit Care Med. 2011;39(6): MFMER slide 45

46 Cyclosporine Author & year Study type Number patients Valeyrie Allanore et al Singh et al Kirchof et al Lee et al Open phase II trial Prospective open trial Cyclosporine treatment 29 3 mg/kg x 10 d, then 2 mg/kg x 10 d, then 1 mg/kg x 10 d 11 3 mg/kg x 7d, then 2 mg/kg x 7 d Mortality, n Other 0 Progression and death rate lower than expected 0 May have encouraging role Retrospective mg/kg x 7 d 1 May have mortality benefit over IVIG Retrospective 44 3 mg/kg x 10 d, then 2 mg/kg x 10 d, then 1 mg/kg x 10 d 3 Statistically insignificant survival benefit compared to supportive care Lee HY, Fook Chong S, Koh HY, Thirumoorthy T, Pang SM. Cyclosporine treatment for Stevens Johnson syndrome/toxic epidermal necrolysis: Retrospective analysis of a cohort treated in a specialized referral center. J Am Acad Dermatol. 2017;76(1): MFMER slide 46

47 TNF-α Inhibitors Proposed mechanism: Ability to inhibit granulysin and TNF α secretion from blister cells 2018 MFMER slide 47

48 TNF-α Inhibitors - Infliximab Author & year Study type Number patients Zarate Correa et al Wojtkiewicz et al Patmanidis et al Case series Case report Case report Treatment Mortality Other 4 Single dose 300 mg infliximab on Day 1 or 2 after admission 1 Single dose 5 mg/kg infliximab after IVIG failure mg methylprednisolone IV bolus followed by 5 mg/kg infliximab IVIG 2g/kg x5 days 0% Disease progression halted in all 4 patients 0% Within 24 hours of infliximab dose onset of new blisters stopped 0% Skin condition markedly stabilized by day 2 of admission Zárate Correa LC, Carrillo Gómez DC, Ramírez Escobar AF, Serrano Reyes C. Toxic epidermal necrolysis successfully treated with infliximab. J Investig Allergol Clin Immunol. 2013;23(1): Wojtkiewicz A, Wysocki M, Fortuna J, Chrupek M, Matczuk M, Koltan A. Beneficial and rapid effect of infliximab on the course of toxic epidermal necrolysis. Acta Derm Venereol. 2008;88(4): Patmanidis K, Sidiras A, Dolianitis K, et al. Combination of infliximab and high dose intravenous immunoglobulin for toxic epidermal necrolysis: successful treatment of an elderly patient. Case Rep Dermatol Med. 2012;2012: MFMER slide 48

49 Randomized, controlled trial of TNF-α antagonist in CTLmediated severe cutaneous adverse reactions Wang CW, Yang LY, Chen CB, et al.; and the Taiwan Severe Cutaneous Adverse Reaction (TSCAR) Consortium. J Clin Invest. 2018;128(3): MFMER slide 49

50 Objectives Primary endpoint: Time required to heal skin erosions and oral mucosa and to begin re epithelialization Secondary monitoring parameters: Adverse events Mortality rates Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): MFMER slide 50

51 Study Methods Single center, prospective, open label, randomized controlled unblinded trial Randomized 1:1 25 mg (or 50 mg if >65 kg) etanercept SQ injection twice a week mg/kg/day prednisolone IV Treated until skin lesions healed 96 patients randomized, 71 completed to efficacy analysis Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): MFMER slide 51

52 Enrollment Inclusion Older than 4 years Diagnosed with probably/definite SJS/TEN Exclusion Pregnant or breastfeeding Allergy to any TNF α inhibitor Active/latent tuberculosis Severe, active infection and septicemia Carriers of active hepatitis B or C Suspected carriers of HIV with CD4 Tcell count <200 Poor compliance or safety concerns Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): MFMER slide 52

53 Baseline Characteristics Characteristic All n= 91 Etanercept n = 48 Corticosteroid n = 43 p value Age, years ± ± ± Sex, n (%) Male 40 (44) 20 (41.7) 20 (46.5) Female 51 (56) 28 (58.3) 23 (53.5) Skin detachment, n (%) BSA 10%, n (%) 35 (38.5) 18 (37.5) 17 (39.5) BSA <10%, n (%) 56 (61.5) 30 (62.5) 26 (60.5) SCORTEN mean 1.85 ± ± Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): MFMER slide 53

54 Results Parameter Etanercept n = 38 Corticosteroid n = 33 p value Median time for skin healing, d Predicted mortality, %, 17.7 ± ± mean Observed mortality, n 4 (8.3) 7 (16.3) (%) GI hemorrhage, % Serious adverse events, n 5 9 Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): MFMER slide 54

55 Conclusion Strengths: randomized controlled trial Limitations: unblinded Conclusion: Etanercept reduced predicted mortality, rates of GI hemorrhage, and time to skin healing in moderate to severe SJS/TEN compared to corticosteroids Further studies in combination with other treatment strategies needed Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF α antagonist in CTL mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3): MFMER slide 55

56 Summary of Adjuvant Therapies Steroids Have been associated with increased infection rates, duration of stay, and mortality Possible beneficial role with short term therapy or as addition to other therapies IVIG Conflicting evidence Most recent studies show no survival benefit over supportive care Cyclosporine Most recent study shows no survival benefit over supportive care More research required TNF α inhibitors Best evidence for mortality benefit Further research required to determine ideal treatment regimen 2018 MFMER slide 56

57 Plasmapheresis Proposed mechanism: Can enhance the removal of medications and activated immune cells from plasma Studies have not consistently shown benefit May be considered if other treatments are failing Ruminski MA, Wisneski SS, Dugan SE. Stevens Johnson syndrome: what a pharmacist should know. US Pharm. 2013; 38(7): Narita YM, Hirahara K, Mizukawa Y, et al. Efficacy of plasmapheresis for the treatment of severe toxic epidermal necrolysis: is cytokine expression analysis useful in predicting its therapeutic efficacy? J Dermatol. 2011; 38: Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens Johnson syndrome/toxic epidermal necrolysis in adults J Plast Reconstr Aesthetic Surg. 2016;69(6):e119 e MFMER slide 57

58 Thalidomide Use is contraindicated in SJS/TEN Double blind, randomized placebo controlled trial (n =12) Mortality increased in thalidomide group vs placebo (83% vs 30%) Trial was discontinued early Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomized comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet. 1998; 352: MFMER slide 58

59 Optimal treatment of SJS/TEN includes supportive care and extended duration corticosteroids. a) True b) False 2018 MFMER slide 59

60 Optimal treatment of SJS/TEN includes supportive care and extended duration corticosteroids. a) True b) False 2018 MFMER slide 60

61 Summary SJS/TEN characterized by full thickness epidermal necrosis and keratinocyte apoptosis Medications are the most common cause of SJS/TEN There is no gold standard of treatment Stop offending agent Supportive care 2018 MFMER slide 61

62 Discussion & Questions 2018 MFMER slide 62

63 Study References 1. Halebian PH, Corder VJ, Madden MR, Finklestein JL, Shires GT. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg. 1986;204(5): Kelemen JJ III, Cioffi WG, McManus WF, et al: Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995; 180: Kakourou T, Klontza D, Soteropoulou F, et al: Corticosteroid treatment of erythema multiforme major (Stevens Johnson syndrome) in children. Eur J Pediatr 1997;156: Forman R, Koren G, Shear NH: Erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis in children: A review of 10 years experience. Drug Saf 2002; 25: Kardaun SH, Jonkman MF: Dexamethasone pulse therapy for Stevens Johnson syndrome toxic epidermal necrolysis. Acta Derm Venereol 2007; 87: Yamane Y, Aihara M, Ikezawa Z: Analysis of Stevens Johnson syndrome and toxic epidermal necrolysis in Japan from 2000 to Allergol Int 2007; 56: Schneck J, Fagot J P, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. 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. 2008;58(1): Yang Y, Xu J, Li F, et al: Combination therapy of intravenous immunoglobulin and corticosteroid in the treatment of toxic epidermal necrolysis and Stevens Johnson syndrome: A retrospective comparative study in China. Int J Dermatol 2009; 48: Bachot N, Revuz J, Roujeau JC: Intravenous immunoglobulin treatment for Stevens Johnson syndrome and toxic epidermal necrolysis: A prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol 2003; 139: Metry DW, Jung P, Levy ML: Use of intravenous immunoglobulin in children with stevens johnson syndrome and toxic epidermal necrolysis: Seven cases and review of the literature. Pediatrics 2003; 112: Brown KM, Silver GM, Halerz M, et al: Toxic epidermal necrolysis: Does immunoglobulin make a difference? J Burn Care Rehabil 2004; 25: Yeung CK, Lam LK, Chan HH: The timing of intravenous immunoglobulin therapy in Stevens Johnson syndrome and toxic epidermal necrolysis. Clin Exp Dermatol 2005; 30: Gravante G, Delogu D, Marianetti M, et al: Toxic epidermal necrolysis and Steven Johnson syndrome: 11 years experience and outcome. Eur Rev Med Pharmacol Sci 2007; 11: Stella M, Clemente A, Bollero D, et al: Toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS): Experience with highdose intravenous immunoglobulins and topical conservative approach. A retrospective analysis. Burns 2007; 33: MFMER slide 63

allergy Asia Pacific Stevens-Johnson syndrome and toxic epidermal necrolysis in Dr. Hasan Sadikin General Hospital Bandung, Indonesia from

allergy Asia Pacific Stevens-Johnson syndrome and toxic epidermal necrolysis in Dr. Hasan Sadikin General Hospital Bandung, Indonesia from pissn -876 eissn -868 Original Article Asia Pac Allergy 6;6:-7 Stevens-Johnson syndrome and toxic epidermal necrolysis in Dr. Hasan Sadikin General Hospital Bandung, Indonesia from 9 Oki Suwarsa *, Wulan