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Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
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Antiepileptic drugs related rash

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Antiepileptic drugs related rash …

Antiepileptic drugs related rash

Presented by Jaichat Mekaroonkamol, MD.

February28, 2014

Published in: Health & Medicine
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  • 1. LOGO AntiEpileptic Drugs Related Rash Jaichat Mekaroonkamol, MD.
  • 2. Contents Adverse effect of AED1 Pathogenesis and cross sensitivity2 Predisposing factors and In vitro assessment 3 Management4
  • 3. Lancet Neurol 2012; 11: 792–802
  • 4. Lancet Neurol 2012
  • 5. Expert Rev. Neurother. 886 10(6), (2010)
  • 6. Adverse reactions CNS AED Non-CNS • Most common • Occur during initiation of Tx • Dose-related • Reversible • Common • Idiosyncratic - Rash - Hepatotoxicity - Hematologic - Renal effect - Metabolic and endocrine
  • 7. • 120 adult (Age > 18 years) • descriptive cross sectional hospital based study
  • 8. Dose related Hussein A, et al. OMJ. 25, 17-21 (2010)
  • 9. Idiosyncheratic N=45 N=42 N=35 N=38 10% Hussein A, et al. OMJ. 25, 17-21 (2010)
  • 10. Types of skin reactions Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
  • 11. Specific reactions to anticonvulsant drugs Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
  • 12. Specific reactions to anticonvulsant drugs Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
  • 13. AED related rash Benign Rash SCARs • Morbilliform / measles- like rashs • SJS • TEN • DRESS
  • 14. Benign Skin Rash • Skin rash extremely common complications of AED – Phenytoin/carbamazepine: 7-12% – Lamotrigine: 8-10% • Morbilliform rashes usually occur within 3-8 wk of drug initiation, more likely to occur when AEDs are started rapidly • Usually be discontinued to minimize risk for a severe skin reaction – Resolve within 1-2 weeks after discontinuing Epilepsia 1999
  • 15. • Retrospective study • 1,890 outpatients with epilepsy • Aged >/= 16 years: 1,649 (87%) • 15 AEDs • Subgroup analysis – Non-AED predictors – with another AED rash – without another AED rash NEUROLOGY 2007;68:1701–1709
  • 16. • Phenytoin 5.9% • Lamotrigine 4.8% • Carbamazepine 3.7% • Topiramate <1% • Valproate 0.7% • Levetiracetam 0.6% • Gabapentin 0.3% NEUROLOGY 2007;68:1701–1709 262/1649 = 15.9%
  • 17. AED predictors NEUROLOGY 2007;68:1701–1709
  • 18. AED predictors NEUROLOGY 2007;68:1701–1709 OR 3.1 (1.8-5.1)
  • 19. AED predictors NEUROLOGY 2007;68:1701–1709 4.1% vs 2.4%
  • 20. • AED-related allergy without rash was not a predictor of AED rash – Hepatitis 42/1,649 = 2.5% – Fever 31/1,649 = 1.8% • The mean time to appearance of a rash was 18.1 (± 10.5)days after starting an AED. NEUROLOGY 2007;68:1701–1709
  • 21. A valuable finding was that the risk of AED linked rash is approximately five-times more likely in patients who have had a previous AED rash (8.8%) than those who did not (1.7%) NEUROLOGY 2007;68:1701–1709
  • 22. Cross-sensitivity of skin rashes • Cross-sensitivity among aromatic AEDs (CBZ, LTG, OXC, PHT, PB) is said to occur in 40–58% of patients • High as 80% in an in vitro assay • Specific cross-sensitivity among CBZ, PHT, and PB may be at least partially explained by the “hapten hypothesis” • LTG: P-I concept Neurology 71 November 4, 2008
  • 23. CBZ, PHT, and PB
  • 24. LTG
  • 25. Neurology 71 November 4, 2008
  • 26. • 3793 outpatients • 3.61% (137/3793) of patients experienced a skin rash • Cross-reactivity rates between certain AEDs are high, especially CBZ and PHT X.-q. Wang et al. Seizure 19 (2010) 562–566
  • 27. X.-q. Wang et al. Seizure 19 (2010) 562–566
  • 28. X.-q. Wang et al. Seizure 19 (2010) 562–566
  • 29. AED related rash Benign Rash SCARs • Morbilliform / measles- like rashs • SJS • TEN • DRESS
  • 30. Harr and French Orphanet Journal of Rare Diseases 2010
  • 31. Histology: SJS • Early – Perivascular mononuclear inflammatory infiltrate comprised primarily of T-lymphocytes. – at the dermoepidermal junction, with lymphocytes clustered around dying basal keratinocytes ("satellitosis") • As the lesions progress – frank subepidermal vesiculation develops, with full thickness epidermal necrosis. • Fully developed SJS – full thickness epidermal detachment with splitting above the basement membrane, minimal inflammatory infiltrate, and normal immunofluorescence. Arch Dermatol. 1992
  • 32. Histology: TEN • The histopathology of TEN is similar in SJS. • In addition – abnormalities of the underlying sweat ducts have been described in TEN, including lymphocytic infiltration, basal cell hyperplasia, and necrosis J Cutan Pathol. 1995
  • 33. DRESS British Journal of Dermatology 2007
  • 34. British Journal of Dermatology 2007
  • 35. AED induced SCARs • Different ethnic populations may have dissimilar risks regarding the development of AED-SCARs due to various genetic backgrounds • CBZ-induced SJS/TEN – 59 cases per 100,000 new users per year in Taiwan. – 2 cases of 100,000 new exposures a year have been reported in the United States – much higher in South-East Asian countries than in Western countries Allergol Int 2010
  • 36. • Retrospective study • 6-year period from January 2003 to December 2009 • At 2 clinical branches of Chang Gung Memorial Hospital • 154 patients with AED induced SCARs Neurology December 6, 2011
  • 37. • CBZ and PHT were the most common causative AEDs – SJS/TEN (67.8%) – DRESS (43.6%) • No SCARs case was caused by nonaromatic AEDs Neurology December 6, 2011
  • 38. • Average latent period in AED-induced SJS/TEN or DRESS was about 20 days ( DRESS has a longer) • Average doses for tolerant controls were much higher Neurology December 6, 2011 AED-SCARs are not associated with the AED dose or exposure duration
  • 39. Neurology December 6, 2011 Most of the patients were well tolerant to nonaromatic AEDs, especially VPA.
  • 40. Prognosis of AED-SCARs Neurology December 6, 2011 • The overall mortality rate was 6.49% (10/154) – TEN: 50% – SJS-TEN: 20% – SJS: 1% – DRESS: 7.7% • PHT was the major AED to cause mortality(8/10 deaths)  PHT-SCARs had more complicated
  • 41. J Investig Allergol Clin Immunol 2013
  • 42. Epilepsy Currents, Vol. 6, No. 2 (March/April) 2006
  • 43. AED AED
  • 44. Predisposing factors • HLA-B 1502 – SJS/TEN induced by CBZ, PHT • HLA-A 3101 – CBZ-ADR in Japanese • CYCP2C19*2 – SCARs from PH • HLA-B 4001 • HLA-B 5801 Protective AED-SJS/TEN
  • 45. HLA-B 1502
  • 46. Screening for HLA-B*1502 has been recommended by the U.S. Food and Drug Administration (FDA) prior to starting CBZ in patients with ancestry from these populations since December 2007 HLA-B 1502
  • 47. Epilepsia 2010
  • 48. • 31 case: 10 AED-SJS, 21 AED-MPE • 50 control: at least 3 months • Age 10-45 years • Exclude patients who developed SJS after simultaneous use of more than one drug • As soon as, they developed cutaneous adverse reactions, all medications were withdrawn Epilepsia, 49(12):2087–2091, 2008
  • 49. • HLA-B 1502 – CBZ-SJS: 100% sensitivity, 80% specificity 43% PPV, 100% NPV – PHT-SJS: 100% sensitivity, 82% specificity 33% PPV, 100% NPV Epilepsia, 49(12):2087–2091, 2008
  • 50. Epilepsia, 54(7):1307–1314, 2013 • 55 case: SJS/TEN • 275 control: at least 3 months • Age 6-77 years
  • 51. Epilepsia, 54(7):1307–1314, 2013
  • 52. Epilepsia, 54(7):1307–1314, 2013 Phenytoin Lamotrigine
  • 53. Epilepsia, 54(7):1307–1314, 2013 Protective AED-SJS/TEN
  • 54. • CYP2C19, a member of cytochrome P450 enzymes • plays an essential role in bioactivating and detoxifying pathways of aromatic AED • most common variant resulting in poor metabolizer are CYP2C19*2(0.27) and CYP19*3(0.02) Pediatr Allergy Immunol 2013 Toxic metabolite
  • 55. Pediatr Allergy Immunol 2013 0-18 yr
  • 56. Pediatr Allergy Immunol 2013 • CYP2C19*2 variant – SCARs from phenobarbital • 42% sensitivity, 77% specificity, 65% PPV, 47% NPV
  • 57. In vivo assessment • Patch tests • Late intradermal reading
  • 58. • 10 subjects (7 females, 3 males), • Age 8 to 42 years (mean age, 21.50 ± 10.99 yr) • Performed 23.50 ± 40.45 months (range, 1 to 120) after the adverse reaction Current Pharmaceutical Design, 2006 • 34 control group subjects (23 females, 11males) • Age from 7 to 55 years (mean age 24.56 ±12.04 years)
  • 59. Current Pharmaceutical Design, 2006 Patch positive
  • 60. Contact Dermatitis 2010: 62: 47–53
  • 61. Drug Safety 2009; 32 (5)
  • 62. • The PPV of the test in optimal conditions was as high as 80–90% depending on the drug tested. • It should be performed 2–6 months after recovery from the date of the ADR for best results Drug Safety 2009; 32 (5)
  • 63. In vitro assessment
  • 64. Lymphocyte transformation tests
  • 65. • 10 subjects (7 females, 3 males), • Age 8 to 42 years (mean age, 21.50 ± 10.99 yr) • Performed 23.50 ± 40.45 months (range, 1 to 120) after the adverse reaction Current Pharmaceutical Design, 2006 • 34 control group subjects (23 females, 11males) • Age from 7 to 55 years (mean age 24.56 ±12.04 years)
  • 66. Current Pharmaceutical Design, 2006 LTT positive Positive responses to aromatic anticonvulsants were observed in 9 (26.5%) of the 34 control group subjects
  • 67. Mol Diagn Ther 2009
  • 68. • Sensitivity of the LTT and the LTA seem to be around 70% and 90% • However, the lack of a gold- standard diagnostic test to prove drug culpability • Timing: 5 weeks to 1 year Mol Diagn Ther 2009
  • 69. Treatment of AED-SCARs 1. Supportive care 2. Corticosteroids 3. IVIG 4. Combination therapy of IVIg and systemic corticosteroids Ciclosporin, TNF antagonists (Infliximab,Etanercept), Plasmapheresis, cyclophosphamide
  • 70. IVIG for TEN • anti-Fas potential of pooled human IVIG in vitro • total IVIG doses of more than 2 g/kg may be of greater benefit
  • 71. IVIG for TEN British Association of Dermatologists 2012
  • 72. Neurology December 6, 2011 1. Corticosteroids – 84.42% for SJS/TEN and DRESS 2. Supportive care: 14.94% 3. IVIG: 0.65% 4. Combination therapy of IVIg and systemic corticosteroids: 6.49%
  • 73. Prognosis of AED-SCARs Neurology December 6, 2011 • The overall mortality rate was 6.49% (10/154) – TEN: 50% – SJS-TEN: 20% – SJS: 1% – DRESS: 7.7%
  • 74. Pediatr Allergy Immunol 2013
  • 75. TAKE HOME MESSAGE • PHT and CBZ are the two drugs which most frequently cause sensitivity • Cross-sensitivity among aromatic AEDs occur in 40-58% • Rarely nonaromatic AEDs induced SCARs • Most of the patients with AED-rashs were well tolerant to nonaromatic AEDs, especially VPA. • CBZ- and PHT-induced SJS, but not MPE, is associated with HLA-B∗1502 allele in Thai population • In vivo and in vitro assesment lack of validated studied • Treatment are controversial
  • 76. LOGO

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