Toxic Epidermal Necrolysis (TEN) & SJS - Dr Pankaj AIIMS, New Delhi

TOXIC EPIDERMAL NECROLYSISPATHOPHYSIOLOGY AND

MANAGEMENTMANAGEMENT

PRESENTER ‐ DR. PANKAJ CHATURVEDI

MODERATOR ‐ DR. B.K. KHAITANALL INDIA INSTITUTE OF MEDICAL SCIENCES(AIIMS),ALL INDIA INSTITUTE OF MEDICAL SCIENCES(AIIMS),

NEW DELHI

INTRODUCTIONINTRODUCTION

TEN and SJSTEN and SJS

• Acute life‐threatening mucocutaneous reactions due to drugsreactions due to drugs.

• Extensive necrosis and detachment of the id iepidermis.

• Systemic toxicity, generalized, erythematousrash, bullae, separation of large sheets of epidermis, mucosal erosions.


SJS TEN


ERYTHEMA MULTIFORMEERYTHEMA MULTIFORME

• Acute , self‐limited, mild, often relapsing mucocutaneous syndromemucocutaneous syndrome.

• Recurrent HSV infection.

• Target ‐shaped plaques predominant on the acral areas and face.

INTRODUCTIONINTRODUCTION• Typical target lesions consist of three

t i tconcentric components:(1) A dusky central disk, or blister(2) Ring of pale edema(3) Erythematous halo

• Herpes iris of Bateman.• Not all lesions of erythema multiforme are ytypical, some display two rings only (raised atypical targets ), but none are flat, which is the typical lesion of SJS‐TEN.


EM

CLASSIFICATIONCLASSIFICATION

• No generally accepted classification of theNo generally accepted classification of the erythema multiforme, SJS and TEN spectrum

• Morphology remains the predominant basis• Morphology remains the predominant basis for disease definitions

C i• Controversy exists


• Bastuji‐Garin et al, divides the spectrum into fiveBastuji Garin et al, divides the spectrum into five categories

(1) Bullous erythema multiforme (EM): epidermal ( ) y ( ) pdetachment involving <10% of the body surface, coupled with localized typical targets or raised atypical targets.

CLASSIFICATIONCLASSIFICATION(2) SJS: epidermal detachment of <10% of the body

f i i ti ith id d th tsurface in association with widespread erythematousor purpuric macules or flat atypical targets .


• 3) SJS/TEN overlap: epidermal detachment of3) SJS/TEN overlap: epidermal detachment of 10% to 30% of the body surface plus widespread purpuric macules or flat atypical targets.

• (4) TEN with spots: epidermal detachment of >30% of the body surface coupled with widespread purpuric macules or flat atypical targets .


• (5) TEN without spots: large sheets of(5) TEN without spots: large sheets of epidermal detachment involving > 10% of the body surface without purpuric macules orbody surface without purpuric macules or target lesions.

These doesn’t occur due to confluence of‐ These doesn t occur due to confluence of smaller lesions.


Clinical and management point of viewClinical and management point of view

• EM ‐ Different disorder (HSV, acralinvolvement young patients)involvement,young patients)

• SJS ‐ <10% BSA

• SJS ‐TEN Overlap ‐ 10‐30% BSA

• TEN ‐ > 30 % BSA

INCIDENCEINCIDENCE

• SJS ‐ 1 to 6 cases/million person yrsSJS 1 to 6 cases/million person yrs.

• TEN ‐ 0.4 to 1.2 cases/million person yrs.

( S d 22 3 )• Any age (AIIMS study mean age‐ 22.3±15.4 yrs)

• M:F ‐ 2:3

• High risk ‐ HIV

‐ CTDCTD

‐Malignancy

MORTALITYMORTALITY

• SJS : 5‐12%

• SJS TEN Overlap : 20 25% (AIIMS 9%)• SJS‐TEN Overlap : 20‐25% (AIIMS‐9%)

• TEN : > 30 % (AIIMS‐26% )

ETIOLOGYETIOLOGY

• Drugs ‐Most casesDrugs Most cases

• Others ‐ Infections (Mycoplasma, HSV)

i i‐ Immunization

‐ BMT

‐ Idiopathic

ETIOLOGYETIOLOGY

DRUGSDRUGS• More than 100 drugs implicated.

• 60‐70 % ‐ Importance of 1 medication est.

• Within 8 weeks (usually 4 to 30 days) after the onset of drug exposure.

• Drugs taken for a long time – minimal riskDrugs taken for a long time minimal risk after 8 wks.

ETIOLOGYETIOLOGYDRUGS

• Anticonvulsants M/C ‐ 35% of total cases

Phenytoin ‐ 45%Phenytoin 45%

Carbamazepine ‐30%

L i i 20%Lamotrigine 20%

Phenobarbitone

Valproic acid ‐ safest Over all risk ‐ 1 to 10 per 10,000 new usersRisk 10 times more in pt previously treated with anticonvulsants

ETIOLOGYETIOLOGY

DRUGSDRUGS• Antibiotics ‐ 33% cases

Cephalosporins M/C‐ 26% cases

Sulfonamides

Quinolones

CyclinsCyclins

ETIOLOGYETIOLOGYDRUGS

• Cross sensitivity Cephalosporins & Penicillines• A reaction to sulfonamide antibiotics does not mean sensitivity to sulfonamide nonantibioticdrugs (thiazide diuretics, sufonylureas, furosemide, or cyclooxygenase‐2 inhibitors) medications.

• Sulfonamide moiety, but only sulfonamide antibiotics have an arylamine group at the N4

iti → hi hl ti it d tposition → highly reactive nitroso product

ETIOLOGYETIOLOGY

DRUGSDRUGSAllopurinol – Single most common drug in Europe

ETIOLOGYDRUGS

ETIOLOGY

DRUGSDRUGSNEWER DRUGS

Nevirapine : RR‐ 22

Lamotrigine : RR‐ 14Lamotrigine : RR 14

Sertaline : RR‐11

P l RR 18Pantoprazole : RR‐18

Tramadol : RR‐ 20

PATHOGENESISPATHOGENESIS

GENETIC FACTORSGENETIC FACTORS

• Significant increase in the human leukocyte antigen (HLA) B12 phenotypeantigen (HLA)‐B12 phenotype.

• Strong association between HLA‐B*1502 and b i i d d SJS/TENcarbamazapine‐induced SJS/TEN.


T‐ CELL ACTIVATIONT CELL ACTIVATION

• Drugs “prohaptens”

Metabolite

Metabolism

Excreted

Detoxification

Excreted


T‐ CELL ACTIVATIONT CELL ACTIVATION

• Drugs “prohaptens”

Metabolite

Metabolism

Metabolite + Endogenous proteins

Detoxification Activation of CD 8

Metabolite + Endogenous proteins

H HLA 1 iHaptens HLA‐1 presentation

PATHOGENESISPATHOGENESIS• HIV patients‐ reduced levels glutathione and cysteine, are

at risk for developing TEN to sulfonamides because of

accumulation of the chemically reactive nitroso product.

• Co‐administration of certain drugs ↑chance of reactions

( ti t b i d l t i i(reactions to carbamazapine and lamotrigine are more

common when given in combination with valproic acid.

The addition of valproic acid ‘‘overloads’’ detoxifying

capacity.)p y )


p‐i conceptp i concept

• pharmacological interaction with immunological receptorimmunological receptor.

• Drug metabolism need not to be abnormal.


APOPTOSISAPOPTOSIS

• Cytotoxic T lymphocytes kill other cells by inducing apoptosis.

• “Cell dies from within”Cell dies from within

• Immunologically silent.

• Once started‐ can not reversed.


APOPTOSISAPOPTOSIS

1. Fas‐Fas ligand (Fas ‐L) pathway

2. Perforin and granzyme pathway

3. TRAIL (TNF‐related apoptosis‐inducing ligand)


Fas‐FasL : APOPTOSISFas FasL : APOPTOSIS


PERFORIN‐GRANZYME PATHWAYPERFORIN GRANZYME PATHWAY

PATHOGENESISPATHOGENESISTRAIL

CLINICAL FEATURESCLINICAL FEATURES

< 10% BSA – SJS< 10% BSA SJS

0% 30% S S S O l10%‐30% BSA _ SJS‐TEN Overlap

>30% BSA _ TEN

CLINICAL FEATURESCLINICAL FEATURESHistory• Within 8 week (usually 4 to 30 days) after the onset of drug exposure.

• Onset delayed in the patients on steroids.

• Prodromal symptoms ‐ 1 to 3 days y p y

• Pain on swallowing and burning or stinging of the eyesthe eyes1/3rd cases begin with ‐ nonspecific symptoms,1/3rd with symptoms of mucous membrane involvement1/3rd with an exanthem


Cutaneous LesionsCutaneous Lesions• Symmetrically distributed on face, upper trunk, proximal extremities, skin tenderness.proximal extremities, skin tenderness.

• The initial skin lesions ‐ erythematous, dusky red, purpuric macules, irregularly shapedp p g y p

• Atypical target lesions with dark centers.• Extensive and diffuse erythema, positive Nikolsky y , p ysign on erythematous zones f/b flaccid blisters, and large areas of exposed, red, oozing dermis



Mucosal Involvement• Mucous membrane involvement (at least two sites) in 90% casessites) in 90% cases.

• Impaired alimentation, photophobia, conjunctival synechiae painful micturitionconjunctival synechiae, painful micturition.

• Oral cavity ,vermilion border ‐ invariably ff daffected.



Mucosal involvementMucosal involvement

• 85% of pt ‐ conjunctival lesions (hyperemia, erosions chemosis photophobia lacrimationerosions, chemosis, photophobia, lacrimation, corneal ulceration, anterior uveitis, purulent conjunctivitis synechiae between eyelids andconjunctivitis, synechiae between eyelids and conjunctiva).

Sh ddi f il f• Shedding of nails ‐ severe forms.


Mucosal InvolvementMucosal Involvement

CLINICAL FEATURESCLINICAL FEATURESExtra‐Cutaneous SymptomsC i l• Constutional symptoms

• Visceral involvement ,pulmonary and digestive li icomplications.

• Early pulmonary complications in 25% pt ‐d b hi l h idyspnea, bronchial hyper secretion, hypoxemia, hemoptysis, expectoration of bronchial mucosal castsbronchial mucosal casts.

• CXR ‐ interstitial syndrome.A i f il A/W i• Acute respiratory failure A/W poor prognosis.


Extra‐Cutaneous SymptomsExtra Cutaneous Symptoms• GIT involvement : less common, epithelial necrosis of the esophagus small bowel colonnecrosis of the esophagus, small bowel, colon‐profuse diarrhea with malabsorption, malena, colonic perforationcolonic perforation.

• Renal involvement ‐ Proteinuria, i lb i i h t i d t imicroalbuminuria, hematuria, and azotemia.

DIAGNOSISDIAGNOSIS

• ClinicalClinical

• Histopathology



First and most important stepFirst and most important step

Stop all the drugs (except the lifesaving drugs)p g ( p g g )


Assessment of patientsAssessment of patients

• Hospitalization (Specialized centre/ Burn care unit) & Barrier nursingunit) & Barrier nursing.

• References ‐ physician, ophthalmologist l l i h i h i d l ipulmonologist, physiotherapist, and plastic

surgeon

• BSA ‐ estimated by the rule of nine.

• Vital signs, urinary output, any clinical evidence g , y p , yof infection or septicemia to be noted


Lab Investigationsg• Complete blood count (N/N , lymphopenia, Neutropenia)

( )• Serum electrolytes (Na+, K+, Ca++, phosphate)• Urinalysis (hematuria, proteinuria)Bl d• Blood sugar

• Liver function tests (deranged in 50%)• Renal function tests• Renal function tests• Chest X‐ray • Blood culture and skin culture to rule out infectionBlood culture, and skin culture to rule out infection

MANAGEMENTMANAGEMENTHistopathology• Epidermal involvement ‐ sparse apoptotic keratinocytes in the suprabasal layers f/b full‐thickness epidermal necrosis and sub epidermalthickness epidermal necrosis and sub‐epidermal detachment .

• Dense mononuclear cell infiltrate of the papillaryDense mononuclear cell infiltrate of the papillary dermis

• Cell‐mediated immunologic reaction(CD8+ g (lymphocytes with features of cytotoxic cells).

• DIF‐ Negative


HistopathologyHistopathology

MANAGEMENTMANAGEMENT• Fluid replacemnent

Parklands formula.Parklands formula.

Fluid requirement = 4 ml/kg body weight x % BSA determined by the rule of nineof nine

75% of this amount is required by the patient of TEN.Half amount is given in first 8 hrs.Half amount is given in next 16 hours.

• Maintenance regimen Urine output is maintained > 1000 —1500 ml/daY.p /Total replacement = urine output +500ml.Total fluids = oral (tube feeding) + intravenous fluids (DNS or normal saline)


Nutritional supportNutritional support

• Oral liquid diet, nasogastric tube or total parenteral nutrition initiated(oral feeding isparenteral nutrition initiated(oral feeding is always preferred).

C l i i 30 35 K l/k d• Caloric requirements ‐ 30‐35 Kcal/kg per day.

• Proteins (1.5 g/kg per day).

• Liquid and semisolid diet.


• Dressing

• Temperature regulation(maintained at 30‐

32°C).)

• Analgesics and antacids


DISEASE SPECIFIC THERAPYDISEASE SPECIFIC THERAPY• No universal consensus on therapy in SJS and TEN.

• Various drugs ‐ corticosteroids, intravenous immunoglobulin (IVIg), cyclosporine, cyclophosphamide, pentoxyfylline, thalidomide, plasmapheresis.

• Very few RCTs.


CORTICOSTEROIDSCORTICOSTEROIDS

• Debatable.

O ll d i l i• Open uncontrolled trials, case series.

• Some authors against use d/t

‐ Risk of infection

‐ Delayed healingDelayed healing


Halebian et al. Annals of Sur 1986;204:5.


GROUP – 1 n=15 GROUP – 2 n=15TREATED WITH STEROIDS(HISTORICAL CONTROLS)

TREATED WITHOUT STEROIDS

5 Survived 10 Survived

11 of 15 cases in gp 2 received steroids over a mean of 3.4 days


JS Pasricha B K Khaitan et al IJD 1996;35:523 7JS Pasricha, B.K.Khaitan et al. IJD 1996;35:523‐7.


• 5 cases of TEN treated with short course of5 cases of TEN treated with short course of high dose steroids, to control the reaction within 24‐48 hrswithin 24 48 hrs.

• Steroids withdrawn in next 7‐10 days.

OUTCOME All i i dOUTCOME‐ All patient survived.


Kardaun et al.Acta Dermatol Venereol 2007;87:144‐8.


• 12 consecutive patients from 1993‐200312 consecutive patients from 1993 2003(7 TEN, 4 SJS‐TEN, 1 SJS)

• All given Dexamethasone pulse for 3 days• All given Dexamethasone pulse for 3 days.• Mean delay between onset & Tt – 2.8 days.1 P ti t di d (SCORTEN di t d f t l• 1 Patient died (SCORTEN predicted fatal outcome in 4).Pt di d d/t b i d d/t t t i• Pt died d/t brain edema d/t metastasis

(Skin healed at the time of death)


Allergology International. 2007;56:419‐425


• 52 cases of SJS 65 cases of TEN retrospectively52 cases of SJS, 65 cases of TEN retrospectively analysed.

• Most cases treated with steroids (in some• Most cases treated with steroids (in some plasmapheresis/IVIG added)

SJS 80 8 % id l (30 8% P l )• SJS ‐ 80.8 % steroids alone (30.8% Pulse)

• TEN‐ 60% steroids alone (29.2% Pulse)

RESULTS ‐ 1 Pt with SJS died (1.9%)

‐ 4 pt with TEN died (6 2%)4 pt with TEN died (6.2%)

(3 had BSA≥90%, 1 BSA ‐70%)


Why earlier studies showed poor outcomeWhy earlier studies showed poor outcome with corticosteroids ??

1) Given too late

2) In a too low dose

3) Given too long


• Corticosteroids – the most effective drugs inCorticosteroids the most effective drugs in stopping the progression of disease.

MANAGEMENTMANAGEMENTBASIC PRINCIPLES FOR GIVING

CORTICOSTEROIDSCORTICOSTEROIDS

1)Withdrawl of causative drug.

2)Administration of a single large dose to control the reaction immediatelyy

(Dexamethasone 8mg‐16mg)

• If doubt in dose err on higher side• If doubt in dose , err on higher side.

MANAGEMENTBASIC PRINCIPLES FOR GIVING

CORTICOSTEROIDS

3) Evaluation of the response to treatment

• Evaluate the response next morning• Evaluate the response next morning.

• Adequate if no new lesions, no increase in size f l i l i h b d k dof prev lesions, lesions has become dusky red,

toxemia disappeared ,patient is alert.

• Inadequate response – increase the dose proportionately, evaluate the response next day.


BASIC PRINCIPLES FOR GIVINGBASIC PRINCIPLES FOR GIVING CORTICOSTEROIDS

4) Early withdrawal of corticosteroids4) Early withdrawal of corticosteroids.

• Tapered from day 2‐3 when reaction is ll dcontrolled.

• Stopped within 7 days.

• Daily reduction of 2‐4 mg dexamethasone.


INTRAVENOUS IMMUNOGLOBULININTRAVENOUS IMMUNOGLOBULIN

• Interferes with Fas‐Fas L interaction and prevents apoptosisprevents apoptosis.

• Anti ‐infectious property( maily has IgG)

• Corrects protein and fluid loss.


INTRAVENOUS IMMUNOGLOBULININTRAVENOUS IMMUNOGLOBULIN

• No conclusive data regarding efficacy.

di h i l• Many studies shown encouraging results.

• Dose‐ 2g/kg.

• Can be given‐ 0.4g/kg/day for 5 days.

• It is available as infusion vial of 100ml with 5gIt is available as infusion vial of 100ml with 5g IVIg or 200ml with 10g IVIg.

• High cost (Rs 5 000 for 5g in India)• High cost (Rs 5,000 for 5g in India)

MANAGEMENT

CYCLOSPORINE

• Inhibits activated T lymphocytes, macrophages and

keratinocyteskeratinocytes.

• Interferes with metabolism of TNF‐α .

• Possesses anti‐apoptotic properties.

3 5 /k d ll i f t 2 k f ll d• 3‐5 mg/kg per day orally or i.v. for up to 2 weeks followed

by weaning over another 2 weeks.

• Encouraging results in reports, larger studies awaited.


THALIDOMIDETHALIDOMIDE

• Proposed as a treatment for TEN because of its potent TNF α inhibitionits potent TNF‐α inhibition.

• Controlled trial was interrupted because of hi h li i h lid id (10higher mortality in thalidomide group (10 out of 12 patients died) compared with placebo (3 f 10 i di d)of 10 patients died).

• Its use is not recommended.


PLASMAPHERESISPLASMAPHERESIS • Removes the drug from the blood.• Inconclusive data to recommend the use• Inconclusive data to recommend the use.CYCLOPHOSPHAMIDEN t f l• Not useful.

OTHERS USED WITHOUT ANY BENIFIT: Pentoxiphylline: N‐Acetyl Cysteine.


• CONTINUING MANAGEMENTCONTINUING MANAGEMENT

‐ Eye care

O l h i‐ Oral hygiene

‐ Skincare

‐ Antibiotics

PROGNOSISPROGNOSIS

SCORTENSCORTEN

• A mathematical tool to assess severity of illness and predict mortalityillness and predict mortality.

• SCORTEN should be computed within the first 24 h f d i i d i d24 hours after admission and again on day three.

PROGNOSISPROGNOSIS

PROGNOSISPROGNOSIS

Other than the SCORTEN

• 1)How long the suspected drug continued after the onset

of SJS‐TEN? (Earlier the drug stopped better is theof SJS TEN? (Earlier the drug stopped, better is the

prognosis)

2)H lf lif f th d (G d ith h t T1/2 d )• 2)Half life of the drug.(Good prog with short T1/2 drugs)

• 3)Delay in referral to a specialized centre(Poor prog)

• 4) Early thrombocytopenia, neutropenia (Poor prog)

• 5)Early antibiotic empirical treatment.(Poor prog)5)Early antibiotic empirical treatment.(Poor prog)

SEQUELAE

• Skin usually heals without scarringSkin usually heals without scarring.

• Mucosal scaring – upto 30% cases

li i• Eye complications.

FINDING OUT THE CULPRIT‐ DRUG PROVOCATION

GOALSGOALS

• Prevent recurrences

l i k d f l• Help patient take drugs safely

• Help doctors prescribe safely for the patient

The greater the severity of the reaction, e g ea e e se e y of e eac o ,

the greater the need to ensure these goals.

FINDING OUT THE CULPRIT‐ DRUG PROVOCATION

If a single drug was ingestedIf a single drug was ingested,

With a consistent time course,

il id ifi dEasily identified. Unnecessary

Multiple drugs ingested

Names of drugs not knowng

Substitutes not easily available Necessary

PREVENTIONPREVENTION

• Survivors and their first degree relativesSurvivors and their first degree relatives should avoid suspected offending agents and related compoundsrelated compounds.

• Drugs of the same pharmacologic class can be used provided they are structurally differentused provided they are structurally different from the culprit drug.

REFERENCES1. Pereira, Mudgil, and Rosmarin et al. Toxic epidermal necrolysis. J Am Acad Dermatol.2007; 56:181‐200.2. R. Wolf et al. Life‐threatening acute adverse cutaneous drug reactions. Clinics in Dermatology. 2005 23, 171–181.3. T.A. Chave et al. Toxic epidermal necrolysis: current evidence, practical management and future directions. BritishJournal of Dermatology 2005 153, pp241–253.4. M Mockenhaupt et al. Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis: Assessment of Medication Riskswith Emphasis on Recently Marketed Drugs. The EuroSCAR‐Study. Journal of Investigative Dermatology (2008) 128,35–44.5 VK Sharma Gomathy Sethuraman Anil Minz Stevens Johnson Syndrome Toxic Epidermal Necrolysis Indian J5. V.K. Sharma, Gomathy Sethuraman, Anil Minz. Stevens Johnson Syndrome, Toxic Epidermal Necrolysis. Indian JDermatol Venereol Leprol 2008 ; 74:3:238‐240.6. Sharma V.K, Sethuraman G., Kumar B. Cutaneous Adverse Drug Reaction Patterns to Antimicrobial Drugs In NorthIndia. J Assoc Physicians India(JAPI).1998; 46: 1012‐5.7. Bastuji‐Garin S et al. SCORTEN: A severity‐of‐illness score for toxic epidermal necrolysis. J Invest Dermatol2000;115:149‐53.2000;115:149 53.8. Guegan S et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis ofepidermal necrolysis. J Invest Dermatol 2006;126:272‐6.9. V. K. Sharma, Sujay Khandpur et al. Guidelines for SJS & TEN and Psoriasis. Therapeutic Guidelines Committee,IADVL‐2007.10. Jagjit S Pasricha, Binod K Khaitan et al. Toxic Epidermal Necrolysis. International J Drematol. 1996;35:7:523‐7.12. Yumiko Yamane et al. Analysis of Stevens‐Johnson Syndrome and Toxic Epidermal Necrolysis in Japan from 2000to 2006. Allergology International. 2007;56:419‐425.13. Sylvia H Kardaun, Marcel F Jonkman. Dexamethasone Pulse Therapy for Stevens‐Johnson Syndrome/ ToxicEpidermal Necrolysis. Acta Dermatol Venereol. 2007;87:144‐148.14.Halebian PH, Corder VJ, Madden MR, et al. Improved burn centre survival of patients with toxic epidermalnecrolysis managed without corticosteroids Ann Surg 1986;205:503 12necrolysis managed without corticosteroids. Ann Surg 1986;205:503–12.15. Y Mukasa, N Craven. Management of toxic epidermal necrolysis and related syndromes. Postgrad Med J2008;84:60–65.16. J. B. van der Meer et al. Successful dexamethasone pulse therapy in a toxic epidermalnecrolysis (TEN) patient featuring recurrent TEN to oxazepam. Clinical and Experimental Dermatology, 26, 654‐656.17. Rook,s Textbook of Dermatology 7th Edition., gy18. Fitzpatrick,s Dermatology in general Medicine 6th & 7th edition.19. Ronni W et al. Treatment of Toxic Epidermal Necrolysis Syndrome With “Disease‐Modifying” Drugs: TheControversy Goes On. Clinics in Dermatology. 2004;22:267–269.20. Stables GI, Lever RS. Toxic epidermal necrolysis and systemic corticosteroids. Br J Dermatol 1993;128:357

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Toxic Epidermal Necrolysis (TEN) & SJS - Dr Pankaj AIIMS, New Delhi