SJS-TEN in Latin America: genetic SJS-TEN in Latin America: genetic

markers, prognosis, usefulness markers, prognosis, usefulness

anti-inflammatory treatment and anti-inflammatory treatment and

recent contributionrecent contribution

Carlos Daniel Serrano Reyes, MDCarlos Daniel Serrano Reyes, MD

Internal Medicine-AllergologyInternal Medicine-Allergology

Fundacion Valle del LiliFundacion Valle del Lili

Cali, ColombiaCali, Colombia

Atlanta, GA, November 9th 2014Atlanta, GA, November 9th 2014

PathophysiologyPathophysiology

Genetic markersGenetic markers

Prognostic scoresPrognostic scores

Anti-inflammatory treatmentAnti-inflammatory treatment

Recent contributionRecent contribution

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Classification of type IV reactionsClassification of type IV reactions

Adapted from Plchler WJ. Immunol Allergy Clin North Am 2004, 24: 373-97Adapted from Plchler WJ. Immunol Allergy Clin North Am 2004, 24: 373-97

Type IV Type IV

aa

Type IV Type IV

bbLTLTHH11 LTLTHH22

MacrophageMacrophage EosinophilEosinophil

TNFTNFαα & INF & INFγγ IL-4 y 5IL-4 y 5

Type IV Type IV

cc

CitoxicityCitoxicity

Keratinocyte apoptosisKeratinocyte apoptosis

CTLCTL

Type IV Type IV

dd

IL-8, GM-IL-8, GM-CSF, CXCL8CSF, CXCL8

NeutrophilNeutrophil

LTLT

Contact Contact dermatitisdermatitis

DRESS DRESS syndromesyndrome

SJS/TENSJS/TEN AGEPAGEP

Torres MJ, et al. J Invest Allergol Clin Immunol 2009, 19: 80-90Torres MJ, et al. J Invest Allergol Clin Immunol 2009, 19: 80-90

NORMAL SKINNORMAL SKIN

Fas (CD95)Fas (CD95)

KeratinocytesKeratinocytes

Apoptosis: interaction Fas - Fas-LApoptosis: interaction Fas - Fas-L

Ito K, et al. Clin Exp dermatol 2004; 29: 679-80Ito K, et al. Clin Exp dermatol 2004; 29: 679-80

Fas-L (CD95-L)Fas-L (CD95-L)

Fas (CD95)Fas (CD95)

SJS/TENSJS/TEN

Fas (CD95)Fas (CD95)Fas (CD95)Fas (CD95)

NOT NOT DAMAGEDAMAGE

CD4 and CD8-CD4 and CD8-dependent dependent activationactivation

DrugDrug

Apoptosis

Apoptosis…Apoptosis…

Chung W-H, et al. Allergollogy International 2010; 59: 325-32

Adapted from Torres MJ, et al. J Invest Allergol Clin Immunol 2009; 19: 80-90Adapted from Torres MJ, et al. J Invest Allergol Clin Immunol 2009; 19: 80-90

ME SJS SJS/TEN TEN ME SJS SJS/TEN TEN

VirusVirus

DrugsDrugs

The less severe the reaction, the more the probability to be caused by a virus !!The less severe the reaction, the more the probability to be caused by a virus !!

Drugs, viral infections and Drugs, viral infections and bullous exanthemasbullous exanthemas

The more severe the reaction, the less the probability to be caused by a virus !!The more severe the reaction, the less the probability to be caused by a virus !!

PathophysiologyPathophysiology

Genetic markersGenetic markers

Prognostic scoresPrognostic scores

Anti-inflammatory treatmentAnti-inflammatory treatment

Recent contributionRecent contribution

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PharmacogeneticsPharmacogenetics

Ferrell PB Jr, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US Ferrell PB Jr, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 2008; 9: 1543-6.FDA recommendations. Pharmacogenomics 2008; 9: 1543-6.

Phillips EJ, Mallal SA. HLA and drug-induced toxicity. Curr Opin Mol Ther. 2009;11: 231-42.Phillips EJ, Mallal SA. HLA and drug-induced toxicity. Curr Opin Mol Ther. 2009;11: 231-42.

Abacavir

AllopurinolCBZ

HLA B5701HLA B5701HLA B5801HLA B5801HLA B1502HLA B1502

Eur J Clin Pharmacol. 2014 Oct 21. [Epub ahead of print]

Clinical features of and genetic predisposition to drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a single Korean tertiary institution patients-investigating the relation between the HLA -B*4403 allele and lamotrigine.Park HJ1, Kim SR, Leem DW, Moon IJ, Koh BS, Park KH, Park JW, Lee JH.

Pharmacogenet Genomics. 2014 Feb;24(2):94-112. doi: 10.1097/FPC.0000000000000021.

HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis.Grover S, Kukreti R.

AimAim: e: evaluate the contribution of common HLA alleles to susceptibility to valuate the contribution of common HLA alleles to susceptibility to

cutaneous ADRs in patients treated with CBZ through a meta-analysiscutaneous ADRs in patients treated with CBZ through a meta-analysis

Twenty elegible studies were identified (720 patients with SJS/TEN)Twenty elegible studies were identified (720 patients with SJS/TEN)

Asians: - HLA B1502: Asians: - HLA B1502: OR 80,70OR 80,70 for bullous lesions (95% CI 45,62-142,77) for bullous lesions (95% CI 45,62-142,77)

- HLA B1511: - HLA B1511: OR 17,43OR 17,43 for bullous lesions (95% CI 3,12-97,40) for bullous lesions (95% CI 3,12-97,40)

- HLA A3101: - HLA A3101: OR 5,65OR 5,65 for bullous lesions (95% CI 2,70-11,78) for bullous lesions (95% CI 2,70-11,78)

- HLA A3101: - HLA A3101: OR 8,58OR 8,58 for for nonnon bullous lesions (95% CI 5,55-13,28) bullous lesions (95% CI 5,55-13,28)

- HLA A2402: - HLA A2402: OR 0,27OR 0,27 for bullous lesions (95% CI 0,11-064) for bullous lesions (95% CI 0,11-064)

Farmacogenetics: ColombiaFarmacogenetics: Colombia

Not published dataNot published data

PathophysiologyPathophysiology

Genetic markersGenetic markers

Prognostic scoresPrognostic scores

Anti-inflammatory treatmentAnti-inflammatory treatment

Recent contributionRecent contribution

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Prognostic scoresPrognostic scores

Bastuji-Garin S, et al. SCORTEN: A severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149-53Bastuji-Garin S, et al. SCORTEN: A severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149-53

Bastuji-Garin S, et al. SCORTEN: A severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149-53Bastuji-Garin S, et al. SCORTEN: A severity of illness score for toxic epidermal necrolysis. J Invest Dermatol 2000; 115: 149-53

Prognostic scores…Prognostic scores…

J Burn Care Res 2011; 32: 237–45

N= 369N= 369

N= 166N= 166N= 369N= 369

SCORTEN in RegiSCAR study…SCORTEN in RegiSCAR study…

Sekula P, et al. J Burn Care Res 2011; 32: 237–45

Sekula P, et al. J Burn Care Res 2011; 32: 237–45Sekula P, et al. J Burn Care Res 2011; 32: 237–45

SCORTEN is good in predicting prognosis (mortality)SCORTEN is good in predicting prognosis (mortality)

Alternative score is less good, but could be used in casesAlternative score is less good, but could be used in cases

of lack of laboratory data in retrospective studies.of lack of laboratory data in retrospective studies.

SCORTEN in RegiSCAR study…SCORTEN in RegiSCAR study…

But…is SCORTEN so good??But…is SCORTEN so good??

Eplasty 2012; 12: e35 (321-31)Eplasty 2012; 12: e35 (321-31)

Von Wild T, et al. Eplasty 2012; 12: e35 (321-31)Von Wild T, et al. Eplasty 2012; 12: e35 (321-31)

Pre-existing illnes and prognosisPre-existing illnes and prognosis

But…is SCORTEN so good??But…is SCORTEN so good??

Severe drug reactions in Latin Severe drug reactions in Latin America (RACGRAD)America (RACGRAD)

To be launched in 2015To be launched in 2015

PathophysiologyPathophysiology

Genetic markersGenetic markers

Prognostic scoresPrognostic scores

Anti-inflammatory treatmentAnti-inflammatory treatment

Recent contributionRecent contribution

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Treatment options: analysis of Treatment options: analysis of the EuroSCAR studythe EuroSCAR study

J Am Acad Dermatol 2008; 58: 33-40J Am Acad Dermatol 2008; 58: 33-40

Scheneck J, et al. J Am Acad Dermatol 2008; 58: 33-40Scheneck J, et al. J Am Acad Dermatol 2008; 58: 33-40

Treatment options: analysis of Treatment options: analysis of the EuroSCAR studythe EuroSCAR study

Glucocorticoids: the prospective Glucocorticoids: the prospective cohort of Roy Pattersoncohort of Roy Patterson’’s groups group

Allergy and Asthma Proc 2000; 21: 101-5Allergy and Asthma Proc 2000; 21: 101-5

Glucocorticoids: the prospective Glucocorticoids: the prospective cohort of Roy Pattersoncohort of Roy Patterson’’s groups group

The largest The largest prospectiveprospective published cohort using CS published cohort using CS

Methylprednisolone 160 to 240 mg/dayMethylprednisolone 160 to 240 mg/day

Tripathi A, et al. Allergy and Asthma Proc 2000; 21: 101-5Tripathi A, et al. Allergy and Asthma Proc 2000; 21: 101-5

Carrillo D, et al. Rev Asoc Colomb Dermatol 2012; 20: 330-6.Carrillo D, et al. Rev Asoc Colomb Dermatol 2012; 20: 330-6.

Relevant citations identified (PUBMED, MEDLINE, EMBASE, Relevant citations identified (PUBMED, MEDLINE, EMBASE,

CDSR, HINARI, CRD, DARE, NHS, EED, HTA, HSRPROL, CDSR, HINARI, CRD, DARE, NHS, EED, HTA, HSRPROL,

HSTAT, HSTAT, Cochrane Skin Group Specialized Register, Cochrane Skin Group Specialized Register,

Cochrane Controlled TrialsCochrane Controlled Trials: 240: 240

Based in article tittle, abstract and key words: Based in article tittle, abstract and key words:

excluded citations: 207excluded citations: 207

Detailed revision in 33 studiesDetailed revision in 33 studies

Excluded studies based on evaluation of whole Excluded studies based on evaluation of whole

article: duplicated (22); no access (1); Mortality not article: duplicated (22); no access (1); Mortality not

measured (1); retrospective study (1)measured (1); retrospective study (1)

Relevant included studies: Open trials Relevant included studies: Open trials

or phase III clinical trials: 8or phase III clinical trials: 8

Carrillo D, et al. Rev Asoc Colomb Dermatol 2012; 20: 330-6.

StudyStudy A-I drugA-I drugInitial Initial scorescore

Observed Observed mortality n(%)mortality n(%)

Score-predicted Score-predicted mortality (%)mortality (%)

In accordance to SCORTEN, it seems that anti-inflmmatory In accordance to SCORTEN, it seems that anti-inflmmatory

treatment (metilprednisolone, IV immunoglobulin and treatment (metilprednisolone, IV immunoglobulin and

cyclosporin), could reduce mortality in patients with cyclosporin), could reduce mortality in patients with

SJS/TEN. SJS/TEN.

ConclusionConclusion

Carrillo D, et al. Rev Asoc Colomb Dermatol 2012; 20: 330-6.

Our experience: glucocorticoidsOur experience: glucocorticoids

AGE (mean years)AGE (mean years) GENDERGENDER SYNDROMESYNDROME OSFCOSFC

39,8 ± 13M F DRESS SJS TEN

3,5 (2,5 – 7,0)4 12 8 5 3

Table 1ATable 1A. . Characteristics of included patients (n=16). OSFC: onset of symptoms to first consultation (median). Characteristics of included patients (n=16). OSFC: onset of symptoms to first consultation (median).

CULPRIT DRUG (S)CULPRIT DRUG (S) TREATMENTTREATMENT PDN (mg) PDN (mg) D of HD of H

ALO NEV FEN OTH CORTICOSTEROIDS

809 ± 556 5 ± 33 3 2 8 *H MP P

13 3 3

Table 1BTable 1B. . Characteristics of included patients (n=16) (cont.). ALO: alopurinol, NEV: nevirapine, FEN: fenitoine, OTH: others. * Characteristics of included patients (n=16) (cont.). ALO: alopurinol, NEV: nevirapine, FEN: fenitoine, OTH: others. * Abacavir, azathioprine, carbamazepine, ceftriaxone, enalapril, lamotrigine, radiocontrast agent and trimethoprim-Abacavir, azathioprine, carbamazepine, ceftriaxone, enalapril, lamotrigine, radiocontrast agent and trimethoprim-sulfamethoxazole. H: hydrocortisone, MP: methylprednisolone, P: prednisone. I: infliximab. PDN: mean of total sulfamethoxazole. H: hydrocortisone, MP: methylprednisolone, P: prednisone. I: infliximab. PDN: mean of total dose of prednisone (equivalent). D of H: days of hospitalization (median). dose of prednisone (equivalent). D of H: days of hospitalization (median).

Bonilla D, et al. Severe drug-induced cutaneous reactions: description of 16 cases and impact of early anti-inflammatory treatment. Bonilla D, et al. Severe drug-induced cutaneous reactions: description of 16 cases and impact of early anti-inflammatory treatment. Poster # 705. XXI World Allergy Congress . Buenos Aires, Argentina. December 6 – 10 2009.Poster # 705. XXI World Allergy Congress . Buenos Aires, Argentina. December 6 – 10 2009.

Diaz JC, et al. Rev Asoc Colomb Dermatol; 2011: 19: 13-9.Diaz JC, et al. Rev Asoc Colomb Dermatol; 2011: 19: 13-9.

Our experience: glucocorticoidsOur experience: glucocorticoids

Hydrocortisone 200 mg/6h IV for 72 hoursHydrocortisone 200 mg/6h IV for 72 hours

19 days19 days

Bonilla D, et al. Severe drug-induced cutaneous reactions: description of 16 cases and impact of early anti-inflammatory treatment. Bonilla D, et al. Severe drug-induced cutaneous reactions: description of 16 cases and impact of early anti-inflammatory treatment. Poster # 705. XXI World Allergy Congress . Buenos Aires, Argentina. December 6 – 10 2009.Poster # 705. XXI World Allergy Congress . Buenos Aires, Argentina. December 6 – 10 2009.

Diaz JC, et al. Rev Asoc Colomb Dermatol; 2011: 19: 13-9.Diaz JC, et al. Rev Asoc Colomb Dermatol; 2011: 19: 13-9.

Our experience: infliximabOur experience: infliximab

Four patients with TEN > 90%

Infliximab 300 mg IV single dose

None died

Complications: sepsis

ResultadosResultados

J Invest Allergol Clin Immunol 2013; 23: 61-3.

Our experience: infliximabOur experience: infliximab

PathophysiologyPathophysiology

Genetic markersGenetic markers

Prognostic scoresPrognostic scores

Anti-inflammatory treatmentAnti-inflammatory treatment

Recent contributionRecent contribution ✔

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CHARACTERISTICS M. ERYTHEMA (N=12) SJS - SJS/TEN - TEN (N=5) TEN (N=9)

SEX 10F, 2M (F 83%) 3F, 2M (F 60%) 7F, 2M (F 77%)

AGE0, 1, 2, 3, 16, 30, 35, 35, 41,

45, 48, 57 (M=32,5)

7, 36, 46, 46, 76

(M=46)

60, 52, 34, 21, 23, 49, 43,

52, 83 (M=23)

CULPRIT DRUG5 (AX), ACICL, FEN, DIP

LEV, CAPE, PANT, CEFTI CBZ, FEN, IBU, AX, CIS3 (FEN), FLU, LMT, FB,

PIRO, NAP, ALO

TREATMENT 9: C 5: C 7: C; 1: IVIG

SECUELAE 1 1 3

VIRAL INFECTION 3 1 0

<20% to 21 to 50% BSA<20% to 21 to 50% BSA >50% BSA>50% BSA

20 out of 26 were female (77%); ME: 83%, SJS: 60%, TEN: 77%20 out of 26 were female (77%); ME: 83%, SJS: 60%, TEN: 77%

Age: most were yAge: most were young adultsoung adults

Antibiotics: 8, anticonvulsivants: 8, NSAIDs: 4, Others: 6Antibiotics: 8, anticonvulsivants: 8, NSAIDs: 4, Others: 6

Antibiotics: ME: 7 (58%), SJS: 1 (20%) , TEN: 0. Antibiotics: ME: 7 (58%), SJS: 1 (20%) , TEN: 0.

Anticonvulsivants: ME: 1 (8,3%), SJS: 2 (40%), TEN: 5 (55%)Anticonvulsivants: ME: 1 (8,3%), SJS: 2 (40%), TEN: 5 (55%)

Concomitant viral infection: ME: 3, SJS: 1, TEN: 0Concomitant viral infection: ME: 3, SJS: 1, TEN: 0

ConclusionsConclusions TEN and SJS are inflammatory conditions and apoptosis of TEN and SJS are inflammatory conditions and apoptosis of

keratinocytes the main pathophysiologic processkeratinocytes the main pathophysiologic process

There is a prognostic score (SCORTEN) that have been validated There is a prognostic score (SCORTEN) that have been validated

in other studies. in other studies.

Genetic screening is usefull in some populations, but its utlity Genetic screening is usefull in some populations, but its utlity

in latins is unknown.in latins is unknown.

Although there are no RCT, anti-inflammatory treatment have Although there are no RCT, anti-inflammatory treatment have

shown to be effective in the management of SJS and TEN shown to be effective in the management of SJS and TEN

Conclusions…Conclusions… Some features were identified in a recent subgroup of Latin Some features were identified in a recent subgroup of Latin

American patients with severe ADRs.American patients with severe ADRs.

Soonly, we will have a record of severe ADRs in Latin

American patients (RACGRAD)

Thank you!Thank you!