Kavish Ihtisham1, Bhargavi Ramanujam1, Shivani Srivastava1, Narinder Kumar Mehra2, Gurvinder Kaur3, Neena Khanna4, Satish Jain5, Sachin Kumar6, Bhavna Kaul7, Raghavan Samudrala7, Manjari Tripathi8. 1. All India Institute of Medical Sciences, Neurology, Neurosciences Centre, Room no-705, 7th floor, 110029, New Delhi, India. 2. Dr. C.G. Pandit National Chair and Ex-head, Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India. 3. Laboratory Oncology, All India Institute of Medical Sciences, New Delhi, India. 4. Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India. 5. Director Indian Epilepsy Centre and President-elect Indian Epilepsy Association. 6. Pharmacology, All India Institute of Medical Sciences, New Delhi, India. 7. Neurology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India. 8. All India Institute of Medical Sciences, Neurology, Neurosciences Centre, Room no-705, 7th floor, 110029, New Delhi, India. Electronic address: mtripathiaiims@gmail.com.
Abstract
PURPOSE: Aromatic antiepileptic drugs (AEDs) are frequently implicated in cutaneous adverse drug reactions (cADRs), a few of which are associated with certain human leukocyte antigen (HLA) alleles in some populations. We aimed to find HLA-associations with AED-related cADRs among North Indians. METHODS: North Indian subjects with cADR due to an AED, and those who were AED-tolerant were recruited as cases and controls, respectively. Genotyping for HLA-A, B and DRB1 were performed. Statistical analysis to compare carrier-rates and allele-frequencies between cases and controls (and healthy population, where necessary), was done for HLA-alleles occurring more than twice in either group. RESULTS: 120 cases {11 - Lamotrigine (LTG), 14 -Valproic acid (VPA), 8 -Levetiracetam (LEV), 35 -Carbamazepine (CBZ) and 52 - Phenytoin (PHT)}, and 250 controls were recruited. Presence of HLA-A*31:01 and HLA-B*51:01 were found to increase the risk of Maculopapular exanthema (MPE) due to CBZ and PHT (OR = 6.38; 95% CI: 1.46-27.75; OR = 4.60; 95% CI: 1.54-13.72, respectively). Among the severe cADRs, HLA-B*57:01(OR = 11.00 95% CI: 1.41-85.81) and HLA-DRB1*07:01 (OR = 7.25; 95% CI: 1.09-48.18) were noted to be significantly associated with CBZ-induced Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN); HLA-B *51:01 was associated with drug reaction eosinophilia and systemic symptoms (DRESS) caused by PHT (OR = 6.90; 95% CI: 1.38-34.29). CONCLUSIONS: We found significant associations of some HLA alleles with specific cADRs to CBZ and PHT in North Indians, which may need to be tested before AED-initiation; only screening for HLA-B*15:02 may not help in this population.
PURPOSE: Aromatic antiepileptic drugs (AEDs) are frequently implicated in cutaneous adverse drug reactions (cADRs), a few of which are associated with certain human leukocyte antigen (HLA) alleles in some populations. We aimed to find HLA-associations with AED-related cADRs among North Indians. METHODS: North Indian subjects with cADR due to an AED, and those who were AED-tolerant were recruited as cases and controls, respectively. Genotyping for HLA-A, B and DRB1 were performed. Statistical analysis to compare carrier-rates and allele-frequencies between cases and controls (and healthy population, where necessary), was done for HLA-alleles occurring more than twice in either group. RESULTS: 120 cases {11 - Lamotrigine (LTG), 14 -Valproic acid (VPA), 8 -Levetiracetam (LEV), 35 -Carbamazepine (CBZ) and 52 - Phenytoin (PHT)}, and 250 controls were recruited. Presence of HLA-A*31:01 and HLA-B*51:01 were found to increase the risk of Maculopapular exanthema (MPE) due to CBZ and PHT (OR = 6.38; 95% CI: 1.46-27.75; OR = 4.60; 95% CI: 1.54-13.72, respectively). Among the severe cADRs, HLA-B*57:01(OR = 11.00 95% CI: 1.41-85.81) and HLA-DRB1*07:01 (OR = 7.25; 95% CI: 1.09-48.18) were noted to be significantly associated with CBZ-induced Stevens Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN); HLA-B *51:01 was associated with drug reaction eosinophilia and systemic symptoms (DRESS) caused by PHT (OR = 6.90; 95% CI: 1.38-34.29). CONCLUSIONS: We found significant associations of some HLA alleles with specific cADRs to CBZ and PHT in North Indians, which may need to be tested before AED-initiation; only screening for HLA-B*15:02 may not help in this population.
Authors: Jason H Karnes; Allan E Rettie; Andrew A Somogyi; Rachel Huddart; Alison E Fohner; Christine M Formea; Ming Ta Michael Lee; Adrian Llerena; Michelle Whirl-Carrillo; Teri E Klein; Elizabeth J Phillips; Scott Mintzer; Andrea Gaedigk; Kelly E Caudle; John T Callaghan Journal: Clin Pharmacol Ther Date: 2020-09-06 Impact factor: 6.875