Disertasi

HLA-B*1502 dan Ekspresi Protein Sitotoksik pada Sindrom Stevens-Johnson/Nekrolitik Epidermal Toksik Akibat CBZ yang Dialami oleh Pasien Epilepsi di Tiga Rumah Sakit di Indonesia. = HLA-B*1502 and cytotoxic protein expression in carbamazepine induced Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis in epilepsy patients in three hospitals in Indonesia.

Latar belakang: Karbamazepin (KBZ) merupakan obat terpilih untuk epilepsi fokal dan dapat digunakan juga untuk pengobatan nyeri neuropatik dan gangguan bipolar, namun dapat menyebabkan reaksi obat yang berat berupa sindrom Stevens-Johnson (SSJ)/nekrolisis epidermal toksik (NET). Saat ini banyak penelitian yang membuktikan terdapat hubungan antara HLA-B*1502 dengan SSJ/NET yang disebabkan oleh KBZ pada orang Asia. Tujuan: Meneliti apakah HLA-B*1502 dapat dijadikan marker terjadinya SSJ/NET yang disebabkan oleh KBZ di Indonesia. Metode: Subjek penelitian direkrut dari poliklinik saraf RSUPN Cipto Mangunkusumo Jakarta, RS Hasan Sadikin Bandung (2 kasus) dan RSUP Prof RD Kandou Manado (2 kasus) pada Mei 2015 sampai dengan Desember 2016. Subjek dengan riwayat SSJ/NET yang disebabkan KBZ dan toleran KBZ dilakukan pemeriksaan typing HLA-B dengan metode sequence specific oligonucleotides probes, dibaca dengan Luminex 200 dan dianalisis dengan perangkat lunak HLA fushion4.0. Dipilih beberapa subjek SSJ/NET dengan HLA-B*1502 positif dan negatif dan toleran dengan HLA-B*1502 positif dan negatif. Subjek yang dipilih ini dilakukan kultur PBMC dengan perlakuan penambahan KBZ dan tanpa perlakuan selama 24 dan 48 jam, kemudian diukur kadar granulisin, granzim B dan perforin dalam medium kultur dengan metode ELISA, untuk melihat peranan HLA-B*1502 dalam terjadinya SJS/NET. Hasil: Total subjek 67 orang, 14 kasus dan 53 toleran. Pada semua subjek dilakukan typing HLA-B, sedangkan kultur dan pemeriksaan kadar granulisin, granzim B dan perforin dilakukan pada 17 subjek (6 SSJ/NET dengan HLA-B*1502 positif dan 3 negatif; 5 toleran HLA-B*1502 positif dan 3 negatif) HLA-B*1502 positif ditemukan pada 8 kasus (57,14%) dan 14 toleran (26,42%), dengan rasio prevalensi 2,73 dan p= 0,0353. Terdapat kecenderungan lonjakan kadar granulisin pada kelompok subjek dengan SSJ/NET dibandingkan kelompok toleran KBZ. Kesimpulan: HLA-B*1502 dapat digunakan sebagai marker pada SSJ/NET karena KBZ.
Kata Kunci: HLA-B*1502, KBZ, SJS/NET, Indonesia


Background: Carbamazepine (CBZ) is a drug of choice for focal epilepsy and can be used for neuropatic pain and bipolar disorder, but it can also causes severe drug reaction in the form of Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). Currently, there are many studies that prove the relationship between HLAB*1502 and SJS/TEN caused by CBZ in Asian ancestry. Objective: To study whether HLA-B*1502 can be used as marker for SJS/TEN caused by CBZ in Indonesia. Method: Subjects were recruited from neurology clinic RSUPN Cipto Mangunkusumo, RS Hasan Sadikin Bandung (two cases), and RSUP Prof. RD Kandou Manado (two cases), from May 2015 to December 2016. Subjects with SJS/TEN history caused by CBZ and CBZ-tolerant went through HLA-B typing examination with sequence specific oligonucleotides probes method, read with Luminex 200 and analyzed with HLA fusion 4.0 software. Some subjects with SJS/TEN with HLA-B*1502 positive and negative, and tolerant subjects with HLA-B*1502 positive and negative, were chosen. These subjects went through PBMC culture with and without CBZ addition for 24 and 48 hours, then granulysin, granzyme B and perforin concentration in culture medium were measured using ELISA method to see the role of HLA-B*1502 in SJS/TEN occurrence. Result: Total number of subjects were 67 with, 14 CBZ induced SJS/NET cases and 53 CBZ-tolerants. All subjects went through HLA typing, while culture and granulysin, granzyme B and perforin examination were conducted in 17 subjects (6 with SJS/TEN with HLA-B*1502 positive and 3 negative; 5 tolerant HLA-B*1502 positive and 3 negative). HLA-B*1502 positive were found in 8 cases (57,14%) and 14 tolerant (26,42%), with prevalence ratio 2,73 p=0,035. There is a tendency increased of granulysin level in CBZ induced SSJ/NET cases. Conclusion: HLA-B*1502 can be used as marker in SJS/TEN induced by CBZ.
Keywords: HLA-B*1502, CBZ, SJS/TEN, Indonesia.


Background: Carbamazepine (CBZ) is a drug of choice for focal epilepsy and can be used for neuropatic pain and bipolar disorder, but it can also causes severe drug reaction in the form of Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN). Currently, there are many studies that prove the relationship between HLA- B*1502 and SJS/TEN caused by CBZ in Asian ancestry. Objective: To study whether HLA-B*1502 can be used as marker for SJS/TEN caused by CBZ in Indonesia. Method: Subjects were recruited from neurology clinic RSUPN Cipto Mangunkusumo, RS Hasan Sadikin Bandung (two cases), and RSUP Prof. RD Kandou Manado (two cases), from May 2015 to December 2016. Subjects with SJS/TEN history caused by CBZ and CBZ-tolerant went through HLA-B typing examination with sequence specific oligonucleotides probes method, read with Luminex 200 and analyzed with HLA fusion 4.0 software. Some subjects with SJS/TEN with HLA-B*1502 positive and negative, and tolerant subjects with HLA-B*1502 positive and negative, were chosen. These subjects went through PBMC culture with and without CBZ addition for 24 and 48 hours, then granulysin, granzyme B and perforin concentration in culture medium were measured using ELISA method to see the role of HLA-B*1502 in SJS/TEN occurrence. Result: Total number of subjects were 67 with, 14 CBZ induced SJS/NET cases and 53 CBZ-tolerants. All subjects went through HLA typing, while culture and granulysin, granzyme B and perforin examination were conducted in 17 subjects (6 with SJS/TEN with HLA-B*1502 positive and 3 negative; 5 tolerant HLA-B*1502 positive and 3 negative). HLA-B*1502 positive were found in 8 cases (57,14%) and 14 tolerant (26,42%), with prevalence ratio 2,73 p=0,035. There is a tendency increased of granulysin level in CBZ induced SSJ/NET cases. Conclusion: HLA-B*1502 can be used as marker in SJS/TEN induced by CBZ.
Keywords: HLA-B*1502, CBZ, SJS/TEN, Indonesia.