LOGO
AntiEpileptic Drugs Related
Rash
Jaichat Mekaroonkamol, MD.
Contents
Adverse effect of AED1
Pathogenesis and cross sensitivity2
Predisposing factors and In vitro
assessment
3
Managem...
Lancet Neurol 2012; 11: 792–802
Lancet Neurol 2012
Expert Rev. Neurother. 886 10(6), (2010)
Adverse reactions
CNS
AED
Non-CNS
• Most common
• Occur during
initiation of Tx
• Dose-related
• Reversible
• Common
• Idi...
• 120 adult (Age > 18 years)
• descriptive cross sectional hospital
based study
Dose related
Hussein A, et al. OMJ. 25, 17-21 (2010)
Idiosyncheratic
N=45 N=42 N=35 N=38
10%
Hussein A, et al. OMJ. 25, 17-21 (2010)
Types of skin reactions
Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
Specific reactions to
anticonvulsant drugs
Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
Specific reactions to
anticonvulsant drugs
Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
AED related rash
Benign
Rash
SCARs
• Morbilliform
/ measles-
like rashs
• SJS
• TEN
• DRESS
Benign Skin Rash
• Skin rash extremely common
complications of AED
– Phenytoin/carbamazepine: 7-12%
– Lamotrigine: 8-10%
•...
• Retrospective study
• 1,890 outpatients with epilepsy
• Aged >/= 16 years: 1,649 (87%)
• 15 AEDs
• Subgroup analysis
– N...
• Phenytoin 5.9%
• Lamotrigine 4.8%
• Carbamazepine 3.7%
• Topiramate <1%
• Valproate 0.7%
• Levetiracetam 0.6%
• Gabapent...
AED predictors
NEUROLOGY 2007;68:1701–1709
AED predictors
NEUROLOGY 2007;68:1701–1709
OR 3.1 (1.8-5.1)
AED predictors
NEUROLOGY 2007;68:1701–1709
4.1% vs 2.4%
• AED-related allergy without rash
was not a predictor of AED rash
– Hepatitis 42/1,649 = 2.5%
– Fever 31/1,649 = 1.8%
• T...
A valuable finding was that the
risk of AED linked rash is
approximately five-times more
likely in patients who have had a...
Cross-sensitivity of skin rashes
• Cross-sensitivity among aromatic AEDs
(CBZ, LTG, OXC, PHT, PB) is said to
occur in 40–5...
CBZ, PHT, and PB
LTG
Neurology 71 November 4, 2008
• 3793 outpatients
• 3.61% (137/3793)
of patients
experienced a skin
rash
• Cross-reactivity
rates between
certain AEDs ar...
X.-q. Wang et al. Seizure 19 (2010) 562–566
X.-q. Wang et al. Seizure 19 (2010) 562–566
AED related rash
Benign
Rash
SCARs
• Morbilliform
/ measles-
like rashs
• SJS
• TEN
• DRESS
Harr and French Orphanet Journal of Rare Diseases 2010
Histology: SJS
• Early
– Perivascular mononuclear inflammatory infiltrate
comprised primarily of T-lymphocytes.
– at the d...
Histology: TEN
• The histopathology of TEN is similar in
SJS.
• In addition
– abnormalities of the underlying sweat ducts ...
DRESS
British Journal of Dermatology 2007
British Journal of Dermatology 2007
AED induced SCARs
• Different ethnic populations may have
dissimilar risks regarding the
development of AED-SCARs due to
v...
• Retrospective study
• 6-year period from January 2003 to
December 2009
• At 2 clinical branches of Chang
Gung Memorial H...
• CBZ and PHT were the most common causative
AEDs
– SJS/TEN (67.8%)
– DRESS (43.6%)
• No SCARs case was caused by nonaroma...
• Average latent period in AED-induced SJS/TEN or
DRESS was about 20 days ( DRESS has a longer)
• Average doses for tolera...
Neurology December 6, 2011
Most of the patients were well tolerant to nonaromatic
AEDs, especially VPA.
Prognosis of AED-SCARs
Neurology December 6, 2011
• The overall mortality rate was 6.49%
(10/154)
– TEN: 50%
– SJS-TEN: 20...
J Investig Allergol Clin Immunol 2013
Epilepsy Currents, Vol. 6, No. 2 (March/April) 2006
AED
AED
Predisposing factors
• HLA-B 1502
– SJS/TEN induced by CBZ, PHT
• HLA-A 3101
– CBZ-ADR in Japanese
• CYCP2C19*2
– SCARs fr...
HLA-B 1502
Screening for HLA-B*1502 has been
recommended by the U.S. Food and
Drug Administration (FDA) prior to
starting CBZ in pati...
Epilepsia 2010
• 31 case: 10 AED-SJS, 21 AED-MPE
• 50 control: at least 3 months
• Age 10-45 years
• Exclude patients who developed SJS a...
• HLA-B 1502
– CBZ-SJS: 100% sensitivity, 80% specificity
43% PPV, 100% NPV
– PHT-SJS: 100% sensitivity, 82% specificity
3...
Epilepsia, 54(7):1307–1314, 2013
• 55 case: SJS/TEN
• 275 control: at least 3 months
• Age 6-77 years
Epilepsia, 54(7):1307–1314, 2013
Epilepsia, 54(7):1307–1314, 2013
Phenytoin
Lamotrigine
Epilepsia, 54(7):1307–1314, 2013
Protective AED-SJS/TEN
• CYP2C19, a member
of cytochrome P450
enzymes
• plays an essential
role in bioactivating
and detoxifying
pathways of arom...
Pediatr Allergy Immunol 2013
0-18 yr
Pediatr Allergy Immunol 2013
• CYP2C19*2 variant
– SCARs from phenobarbital
• 42% sensitivity, 77% specificity, 65% PPV, 4...
In vivo assessment
• Patch tests
• Late intradermal reading
• 10 subjects (7 females, 3 males),
• Age 8 to 42 years (mean age, 21.50 ± 10.99 yr)
• Performed 23.50 ± 40.45 months (ran...
Current Pharmaceutical Design, 2006
Patch positive
Contact Dermatitis 2010: 62: 47–53
Drug Safety 2009; 32 (5)
• The PPV of the test in optimal
conditions was as high as 80–90%
depending on the drug tested.
• It should be performed 2...
In vitro assessment
Lymphocyte transformation tests
• 10 subjects (7 females, 3 males),
• Age 8 to 42 years (mean age, 21.50 ± 10.99 yr)
• Performed 23.50 ± 40.45 months (ran...
Current Pharmaceutical Design, 2006
LTT positive
Positive responses to aromatic anticonvulsants were
observed in 9 (26.5%)...
Mol Diagn Ther 2009
• Sensitivity of the LTT and the LTA
seem to be around 70% and 90%
• However, the lack of a gold-
standard diagnostic test...
Treatment of AED-SCARs
1. Supportive care
2. Corticosteroids
3. IVIG
4. Combination therapy of IVIg and
systemic corticost...
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 b...
IVIG for TEN
British Association of Dermatologists 2012
Neurology December 6, 2011
1. Corticosteroids
– 84.42% for SJS/TEN and DRESS
2. Supportive care: 14.94%
3. IVIG: 0.65%
4. ...
Prognosis of AED-SCARs
Neurology December 6, 2011
• The overall mortality rate was 6.49%
(10/154)
– TEN: 50%
– SJS-TEN: 20...
Pediatr Allergy Immunol 2013
TAKE HOME MESSAGE
• PHT and CBZ are the two drugs which most
frequently cause sensitivity
• Cross-sensitivity among aromat...
LOGO
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Antiepileptic drugs related rash
Upcoming SlideShare
Loading in...5
×

Antiepileptic drugs related rash

555
-1

Published on

Antiepileptic drugs related rash

Presented by Jaichat Mekaroonkamol, MD.

February28, 2014

Published in: Health & Medicine
0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
555
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
42
Comments
0
Likes
2
Embeds 0
No embeds

No notes for slide

Antiepileptic drugs related rash

  1. 1. LOGO AntiEpileptic Drugs Related Rash Jaichat Mekaroonkamol, MD.
  2. 2. Contents Adverse effect of AED1 Pathogenesis and cross sensitivity2 Predisposing factors and In vitro assessment 3 Management4
  3. 3. Lancet Neurol 2012; 11: 792–802
  4. 4. Lancet Neurol 2012
  5. 5. Expert Rev. Neurother. 886 10(6), (2010)
  6. 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. 7. • 120 adult (Age > 18 years) • descriptive cross sectional hospital based study
  8. 8. Dose related Hussein A, et al. OMJ. 25, 17-21 (2010)
  9. 9. Idiosyncheratic N=45 N=42 N=35 N=38 10% Hussein A, et al. OMJ. 25, 17-21 (2010)
  10. 10. Types of skin reactions Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
  11. 11. Specific reactions to anticonvulsant drugs Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
  12. 12. Specific reactions to anticonvulsant drugs Herbert AA, Ralston JP.. J Clin Psychiatry. 2001;62 (Suppl 14):22-26
  13. 13. AED related rash Benign Rash SCARs • Morbilliform / measles- like rashs • SJS • TEN • DRESS
  14. 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. 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. 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. 17. AED predictors NEUROLOGY 2007;68:1701–1709
  18. 18. AED predictors NEUROLOGY 2007;68:1701–1709 OR 3.1 (1.8-5.1)
  19. 19. AED predictors NEUROLOGY 2007;68:1701–1709 4.1% vs 2.4%
  20. 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. 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. 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. 23. CBZ, PHT, and PB
  24. 24. LTG
  25. 25. Neurology 71 November 4, 2008
  26. 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. 27. X.-q. Wang et al. Seizure 19 (2010) 562–566
  28. 28. X.-q. Wang et al. Seizure 19 (2010) 562–566
  29. 29. AED related rash Benign Rash SCARs • Morbilliform / measles- like rashs • SJS • TEN • DRESS
  30. 30. Harr and French Orphanet Journal of Rare Diseases 2010
  31. 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. 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. 33. DRESS British Journal of Dermatology 2007
  34. 34. British Journal of Dermatology 2007
  35. 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. 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. 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. 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. 39. Neurology December 6, 2011 Most of the patients were well tolerant to nonaromatic AEDs, especially VPA.
  40. 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. 41. J Investig Allergol Clin Immunol 2013
  42. 42. Epilepsy Currents, Vol. 6, No. 2 (March/April) 2006
  43. 43. AED AED
  44. 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. 45. HLA-B 1502
  46. 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. 47. Epilepsia 2010
  48. 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. 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. 50. Epilepsia, 54(7):1307–1314, 2013 • 55 case: SJS/TEN • 275 control: at least 3 months • Age 6-77 years
  51. 51. Epilepsia, 54(7):1307–1314, 2013
  52. 52. Epilepsia, 54(7):1307–1314, 2013 Phenytoin Lamotrigine
  53. 53. Epilepsia, 54(7):1307–1314, 2013 Protective AED-SJS/TEN
  54. 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. 55. Pediatr Allergy Immunol 2013 0-18 yr
  56. 56. Pediatr Allergy Immunol 2013 • CYP2C19*2 variant – SCARs from phenobarbital • 42% sensitivity, 77% specificity, 65% PPV, 47% NPV
  57. 57. In vivo assessment • Patch tests • Late intradermal reading
  58. 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. 59. Current Pharmaceutical Design, 2006 Patch positive
  60. 60. Contact Dermatitis 2010: 62: 47–53
  61. 61. Drug Safety 2009; 32 (5)
  62. 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. 63. In vitro assessment
  64. 64. Lymphocyte transformation tests
  65. 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. 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. 67. Mol Diagn Ther 2009
  68. 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. 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. 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. 71. IVIG for TEN British Association of Dermatologists 2012
  72. 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. 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. 74. Pediatr Allergy Immunol 2013
  75. 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. 76. LOGO
  1. Gostou de algum slide específico?

    Recortar slides é uma maneira fácil de colecionar informações para acessar mais tarde.

×