With the advancements in pharmacogenetics, potential genetic associations with severe cutaneous adverse drug reactions (SCAR)—which include Stevens- Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)—have been proposed. Lamotrigine is one of the 2 anticonvulsants found to be highly associated with SJS/TEN from the 2008 EuroSCAR study. Several studies worldwide have looked at the association of specific human leukocyte antigen (HLA) alleles with lamotrigine-induced SCAR in patients from different geographical and ethnic origins.
In our study, data from patients at 2 tertiary hospitals in Singapore—Singapore General Hospital and National University Hospital—which are part of the ongoing pharmacogenetics study of adverse drug reactions (ADR) of serious skin rash, in collaboration with the Health Sciences Authority (HSA) were retrospectively analysed. A total of 6 patients with a diagnosis of lamotrigine-induced SCAR from January 2003 to September 2018 were recruited. Recruitment was based on physician identification of eligible patients, and written informed consent for blood collection for HLA testing and for medical records access.
Clinical assessments and treatment were conducted by specialist dermatologists correlating the clinical presentation and morphology with temporal drug history, and histology specimens if performed. The percentage of body-surface-area involvement was used to differentiate between SJS (<10%), SJS/TEN overlap (10–30%) and TEN (>30%). Eligibility and identification of the causative drug was made based on “certain” or “probable” causality as per the World Health Organization Uppsala Monitoring Centre (WHO-UMC) criteria and Algorithm for Assessment of Drug Causality (ALDEN) scoring.1 Patients with “possible” causality were excluded.
HLA genotyping was performed by the Singapore Immunology Network, according to verified methods by Pozzi et al.2 Data obtained by sequencing were interpreted by Sequencing Analysis Software (Applied Biosystems, Waltham, US) and checked against a library of HLA sequences and alleles according to the Immunogenetics (IMGT)/HLA Database.3
All of the recruited patients with lamotrigine-induced SCAR had SJS (83%) or TEN (17%). None presented with drug reaction with eosinophilia and systemic symptoms (DRESS) or acute generalised exanthematous pustulosis. None developed significant liver or systemic abnormalities (Table 1). Four of the 6 patients were female. Lamotrigine was determined as the probable single causative agent, with latency of 11–31 days (mean 2.8 weeks), and mean ALDEN score was 4. Three patients had skin biopsies performed, which were consistent with the diagnosis of SJS/TEN, with necrolytic keratinocytes and epidermal detachment. The mean severity-of-illness Score for TEN (SCORTEN) was 1.9 (range 1–3).
Table 1. Demographics of patients with lamotrigine-induced SJS or TEN
|No. of patients||N=6
|Age, years, mean±SD, (range)||36±13 (20–57)|
|History of cutaneous adverse reaction to drugs||1 (17)|
|Mean dosage, mg, mean±SD, (range)||27.1±12.3 (12.5–50)|
|Indication for lamotrigine
|Temporal lapse in weeks from start of drug to onset of reaction, mean±SD (range)||2.83±1.17 (2–4)|
|Concurrent valproate administration||3 (50)|
|BSA affected in %, mean±SD (range)||16±20 (8–58)|
|Topical steroids||6 (100)|
|Intravenous immunoglobulin||0 (0)|
SD: standard deviation; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis
Half of the patients (50%) were prescribed lamotrigine for epilepsy, while other medical indications included bipolar disorder (33%) and depression (17%). Lamotrigine was most commonly prescribed at a dose of 25mg daily. All reported the use of concomitant drugs, with valproate being administered concurrently in 50%; and fluoxetine and tranexamic acid in 17%, which were stopped as they were non-essential. ALDEN scoring was performed to help identify the causative drug. Only 1 patient (17%) had reported prior drug allergy to another drug (levofloxacin).
All of the patients were treated with topical steroids such as 0.1% betamethasone valerate or mometasone furoate cream. Two patients (33%) required systemic ciclosporin that was started at 4mg/kg/day and stopped on resolution. None was treated with intravenous human normal immunoglobulin or systemic corticosteroids. All of the patients recovered, with no systemic complications on follow-up. All developed varying degrees of post-inflammatory hyperpigmentation over the previous sites of dermatosis. One patient had persistent oral erosions for 1 month, which resolved after topical triamcinolone application. Beau’s lines were noted on 1 patient’s nails 3 months later. None developed mucocutaneous strictures or vision abnormalities.
There are few studies on lamotrigine-induced SCAR in Southeast Asia. Wang et al. previously proposed risk factors for lamotrigine-induced SCAR as being rapid drug titration, concurrent valproate administration, prior history of anticonvulsant-associated rash, female, and age less than 13 years.4 Our study has revealed supporting data, whereby majority of patients were female (83%), and half were taking valproate concurrently. As previous reports of lamotrigine-induced SCAR worldwide have been seen in high dosages of more than 100mg/day, some advocate the use of low dose initiation and slow drug escalation.4,5 All of our patients developed SCAR despite being on low doses of lamotrigine with an average of 25mg/day. In future studies, we hope to look at the impact and value of low dosages of anti-epileptics in an Asian context.
Genetic factors are recognised as major risk factors in the development and predisposition of SCARs, with distinct HLA alleles linked with different populations; and the identification of associated alleles can have great utility in the management of SCARs. In Singapore, there are 3 major ethnic groups, with Chinese being the majority (75%), followed by Malays (14%) and Indians (9%). Singapore’s HSA, in collaboration with several public healthcare institutions, embarked on a programme in 2009 on the analysis of DNA samples from patients who had experienced drug-induced SCARs, and to capture the phenotypic data associated.6 The validation of the association of HLA-B*1502 allele with carbamazepine-induced SCAR led to the Ministry of Health’s implementation and subsidy of HLA-B*1502 testing in 2013 as the standard-of-care prior to the initiation of carbamazepine, which contributed to a reduction in carbamazepine-induced SJS/TEN in Singapore by 92%.7
In our case series (Table 1), there was no specific HLA allele that was demonstrated to be carried by the majority of patients (defined as greater than 50%). Half of the patients were found to carry HLA-DRB1*1202. Two patients of Chinese ethnicity were found to carry HLA-A*2402, while another one-third had HLA-A*3303.
In a 2018 meta-analysis, Deng et al. proposed that HLA-B*1502 appears to be the risk allele for lamotrigine-induced SJS/TEN in the Asian population (pooled odds ratio [OR] 2.4, 95% confidence interval [CI] 1.20–4.78, P=0.01), while HLA-A*2402 is statistically associated with a susceptibility to either SJS/TEN or maculopapular exanthems (MPE) from lamotrigine8 (Table 2). A systematic review of 5 studies with drug-tolerant and population controls found a statistically significant association between the HLA-A*2402 allele and lamotrigine-induced cutaneous-ADR (cADR) (OR 1.94, 95% CI 1.06–3.54, P=0.03).9 However, both meta-analyses defined cADRs as inclusive of MPEs, and not solely SCARs. It is noteworthy that only 1 patient in our case series had HLA-B*1502 (data not shown), and 2 patients had HLA-A*2402.
Table 2. Comparison of observations of lamotrigine-related SCARs from Asia
|No.||Reported HLA allele(s)|
|An et al.
|China||3||HLA-B*1502 was present in 1 out of 3 (33.3%) cases|
|Hung et al.
|Taiwan||6||HLA-B*1502 was present in 2 out of 6 (33.3%) cases|
|Cheung et al.
|Hong Kong, China||6||HLA-B*1502 was present in 2 out of 6 (33.3%) cases|
|Kwan et al.
|Hong Kong, China||6||HLA-B*1502 was present in 2 out of 6 (33.3%) cases|
|Wang et al.
|China||7||HLA-DRB1*1501 and HLA-B*1502 were present in 4 and 2 out of 7 (57.1% and 28.6%) cases, respectively|
|Srivastava et al. (2017)15||India||3||HLA-B*1502 was present in 1 out 3 (33.3%) cases|
|Shi et al.
|China||22||HLA-A*2402 was present in 10 out 22 (45.5%) cases|
|Kim et al.
|South Korea||18||HLA-A*3101 was present in 8 out of 18 (44.4%) cases|
|Koomdee et al.
|Thailand||4||HLA-A∗0207 and HLA-B∗1502 were reported in 2 and 1 out of 4 (50% and 25%) cases, respectively|
SCAR: Severe cutaneous adverse drug reaction
Superscript numbers: refer to REFERENCES
Note: Single studies that defined cutaneous adverse drug reactions as maculopapular exanthems with lamotrigine were not included.
While we did not identify a single major HLA-related genetic risk factor for lamotrigine-induced SCAR, this is preliminary data and can help guide further larger-scale studies with higher statistical power, and with comparison between drug-tolerant control groups in our Singapore population.
The authors would like to thank the coordinators of the pharmacogenetics study for their help and support. The authors declare no conflict of interest and no financial disclosure.
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- Koomdee N, Pratoomwun J, Jantararoungtong T, et al. Association of HLA-A and HLA-B alleles with Lamotrigine-Induced cutaneous adverse drug reactions in the Thai population. Front Pharmacol 2017;8:879.