Cutaneous Adverse Drug Reactions to Lamotrigine and Human Leukocyte Antigen Typing in North Indian Patients: A Case Series.

Cutaneous adverse drug reaction (cADR) has limited epidemiological data in India. The older antiepileptic drugs, i.e., carbamazepine, phenytoin, valproic acid, phenobarbitone, etc., induce severe cADRs that have a strong associated with human leukocyte antigen (HLA)-related genetic risk factors. There is also evidence of association of certain HLA alleles with lamotrigine (LTG)-induced cADRs, but this has not been reported in the Indian population. Here, we report case series of three patients with LTG-induced "Stevens-Johnson syndrome (SJS)." Their HLA-B typing was also performed which showed the presence of HLA-B*15:02 in one case with SJS.

INTRODUCTION

Aromatic anticonvulsant drugs are one of the most common causes of cutaneous adverse drug reactions (cADRs) that range from mild maculopapular exanthema (MPE) to severe life-threatening toxic epidermal necrolysis (TEN) and drug hypersensitivity syndrome.[1] Lamotrigine (LTG) is an efficacious antiepileptic drug (AED) in refractory partial and generalized seizures; it also acts as an effective mood stabilizer.[2] However, cADR to LTG is infrequent; studies report the incidence rate of between 0.1% and 1% for severe and about 10% for nonsevere cADR.[3] The chances of these adverse effects are higher when LTG is combined with valproate.[45]

Severe cutaneous adverse reactions (SCAR) due to LTG have been shown to be associated with human leukocyte antigen (HLA) alleles in the population.[67] Although there are a few reported cases of LTG-induced Stevens-Johnson Syndrome (SJS) in Indian patients with epilepsy,[89] there is no study with HLA typing. Here, we report a series of three cases with severe cADRs to LTG along with their HLA typing.

CASE REPORTS

Case 1

A 16-year-old female student presented with absence seizures for 2 years of age and no significant past or family history of epilepsy or allergic disorder. The computerized tomography (CT) head and magnetic resonance imaging (MRI) of the brain were found to be normal; electroencephalography (EEG) was abnormal with diffuse cerebral dysfunction. She had been treated with clobazam 10 mg/day OD, for 1.5 years, but was still experiencing seizures about one to two in a day; therefore, LTG was added, starting with 25 mg a day, with weekly escalation, up to a dose of 100 mg/day. After 2 weeks of adding LTG, she developed fever, headaches, chills, and rash all over the body; the patient presented to the dermatology outpatient department (OPD) after 1 week of onset of the symptoms.

On examination, maculopapular lesions involving the genitals associated with itching were seen, which then spread to the trunk and then extremities in the next 3 days [Figure 1]. They became tender, and the erythematous, partially blanchable lesions took on a dusky hue over the trunk, upper limb, lower limb, and progressed to involve the face and lips (crusted plaques). No involvement of the oral cavity was noted nor were there any vesicular lesions. On the basis of history and clinical examination, a diagnosis of TEN was made and LTG was discontinued immediately and admitted under the dermatology department. LTG was stopped, and she was started on levetiracetam 500 mg twice a day, continued on clobazam 10 mg/day, intravenous steroids, fluids, and antibiotics. With medications and supportive care, the patient improved without any further complications.

Figure 1

Large erythematous lesions on the left arm of case 1

Case 2

A 54-year-old housewife, known case of bipolar disorder with anxiety, presented to the neurology OPD. She was on valproate, fluoxetine, and olanzapine but for the past 3–4 months had worsened despite being on these three medications. Mirtazapine and LTG drugs were added by the psychiatrist, 15 days after which she complained of fever, pain in both ears, and presented to the dermatology OPD with rashes. On examination multiple discrete papules which were erythematous to hyper pigmented were seen all over the body;also seen were mucosal congestion and conjunctival involvement (matted eye lashes with crusting). There was also necrosis in nasal, oral (hemorrhagic crusting on lips), and genital (moist gray-white slough on the vaginal mucosa) areas [Figure 2]. There was no past or family history of any allergies. On the basis of clinical evaluation, the patient was diagnosed with SJS. LTG was stopped immediately and appropriate treatment was initiated. Patient's general condition improved, and on discharge, she was given antibiotic, steroid, and antihistaminic medications.

Figure 2

Multiple discrete erythematous, red macules on the limb of case 2

Case 3

A 16-year-old boy, known case of juvenile myoclonic epilepsy, presented to the neurology OPD with generalized maculopapular rash [Figure 3], fever, and facial puffiness. He was on LTG 250 mg TDS, clobazam 10 mg OD, and valproate 200 mg (morning) 400 mg (evening) for 1 year. Subsequently, he developed erythematous rashes over the face, neck, trunk, arms, and legs followed by painful ulcers in the oral cavity and encrustations on the lips. History revealed that no such lesions occurred earlier. His neurological examinations, CT head and MRI, were found to be within normal limits. EEG was abnormal and suggestive of generalized epilepsy. Physical examination showed multiple round erythematous plaques on the face, neck, trunk, and extremities, some of which were tender. On oral examination, there was limited mouth opening and erythematous crusted areas on both the lips due to inflammation and ulceration. Based on the history and clinical presentation, a diagnosis of SJS was made. As the Pre-assumption was LTG, the drug was withdrawn immediately and the dose of clobazam was increased. The patient was admitted to dermatology ward and treated with cyclosporine and methylprednisolone and intravenous fluids. His condition improved during the next 2 weeks; he eventually recovered and continued follow-up on an outpatient basis.

Figure 3

Macular crusting over the trunk of case 3

Human leukocyte antigen genotyping

Five ml of blood sample was drawn from the patients; Deoxyribonucleic acid (DNA) was extracted and checked for quality and quantity on 0.8% agarose gel and spectrophotometer. Genotyping was done by Luminex technology by polymerase chain reaction (PCR) with sequence-specific primers (LabType SSO HLA-B kits; One Lambda, United States). High-resolution typing was done by One Lambda PCR kit by the standard protocol of the manufacturer. The PCR products were run on LabScan 100 analyzer for the detection of four-digit HLA alleles.

DISCUSSION

Associations between the HLA-A*30:01 and B*13:02 alleles and LTG-induced MPE have been reported in Han Chinese.[10] Among other population groups, the HLA-B*58:01, A*68:01, Cw*07:18, DQB1*06:09 and DRB1*13:01 alleles were reported to be weakly associated with LTG-induced cADR in patients of European origin,[11] and the HLA A*02:01:01/B*35:01:01/C*04:01:01 haplotype has been suggested as a biomarker for LTG-induced MPE in Mexican mestizo patients.[12] Here, we report a series of three North Indian patients who had severe cADRs (SJS and TEN) to LTG. The alleles associated were HLA-B*15:02/52:01, HLA-B*15:02/ 44:03 and HLA-B*13:01/13:01 homologous [Table 1].

Table 1

Clinical characteristics and genotype in cases with lamotrigine-induced Stevens-Johnson syndrome

In the study done by Cheung et al. on 55 patients of cADRs due to various AEDs over 16.5 years, different HLA-B alleles were detected, and among all cases, HLA-B*1502, HLA-B*13:01, HLA-B*38:02, and HLA-B*46:01 were found to be the most common alleles found in Han Chinese patients.[6] Park et al., In a study of 5802 Korean patients, found 26 types of HLA-B alleles, the most common alleles being HLA-B*15 and HLA-B*44. After high-resolution HLA typing done in some cases, the alleles which were found to be associated with SCAR were HLA-B*44:03, HLA-B*51:01, and HLA-B*15:01.[7] Another study by Kim et al. on 18 patients with LTG-induced SCAR, HLA-A*31:01 was significantly higher among SCAR patients compared with the LTG-tolerant group and general Korean population.

HLA-B*15:02 Allele was found in one of our patients; the association of this allele has been reported in several studies associated with LTG-induced cADRs.[613] According to a meta-analysis done by Zeng et al., there are only six studies that have looked into the association of HLA gene with LTG -induced SJS/TEN, of which four found an association with HLA-B*15:02 in Han Chinese cases While the other two (in the European population) did not.[14] Furthermore, positive association was found between HLA B*1502 and LTG-SJS/TEN in the Han Chinese Population of in Hong Kong, Taiwan, and Mainland China in another meta-analysis.[15] Although we also found HLA-B*15:02 in one of our LTG-induced SJS/TEN patients, a case–control study must be done in the Indian population to look for the association of specific HLA alleles in LTG-induced cADRs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.