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Severe Cutaneous Adverse Reactions in a tertiary care hospital with perspectives on pharmacogenomics and personalised medicine
*Corresponding author: J. V. Jenisha, Department of Pharmacology, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth, Puducherry, India. jeni17stephen@gmail.com
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Received: ,
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How to cite this article: Srinivasan A, Ananthy V, Jenisha JV, Kumarappan M, Shanmugam S, Karthik V. Severe Cutaneous Adverse Reactions in a tertiary care hospital with perspectives on pharmacogenomics and personalised medicine. Indian J Physiol Pharmacol. doi: 10.25259/IJPP_52_2025
Abstract
Severe Cutaneous Adverse Reactions (SCAR) are life-threatening adverse drug reactions (ADRs) associated with the systemic administration of various medications. Prompt identification and withdrawal of the causative drug, followed by a multidisciplinary mode of management, is essential to prevent morbidity and various complications of SCARs. The presence of certain human leucocyte antigens or genetic variants is associated with an increased risk of the development of SCARs. Knowledge of these genetic variations will go a long way in preventing these reactions. This is a retrospective case series based on SCARs reported to a regional ADR monitoring centre over a period of 1 year, with a relevant review of literature. This case series discusses the risk factors associated with SCARs and the role of personalised medicine in identifying the associated factors and preventing morbidity and mortality from SCARs.
Keywords
Adverse drug reaction
Drug reaction with eosinophilia and systemic symptoms
Pharmacogenomics
Severe cutaneous adverse reaction
Toxic epidermal necrolysis
INTRODUCTION
Cutaneous adverse drug reactions (CADRs) or toxidermia are CADR produced by the systemic administration of various medications. They have a wide variety of clinical presentations, beginning from mild maculopapular lesions to moderate and severe reactions.[1]
The above adverse drug reactions (ADRs), which are severe and potentially life-threatening, are labelled as severe cutaneous adverse reactions (SCARs).[2] These include conditions such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalised exanthematous pustulosis (AGEP) and generalised bullous fixed drug eruption which are very challenging in clinical practice because of their complications and possible risk of mortality.[1-3] These reactions are often induced by medications, and identification of the causative drug is important for proper management of the condition and prevention of further harm. This case series includes five different cases of drug-induced SCAR associated with different drugs reported to an ADR Monitoring Centre in a tertiary care hospital over a period of 1 year. Whenever there were incomplete data from these spontaneous ADR reports in any case, further data were collected and verified from a retrospective review of case sheets from the medical records department. Causality assessment using the World Health Organization-Uppsala Monitoring Scale (WHO-UMC) and Naranjo scale has been performed for all the cases.[4,5]
Each case shows the significance of diagnosis and proper clinical assessment, early withdrawal of drugs and proper treatment strategies such as systemic corticosteroids and supportive care. The role of certain human leucocyte antigens (HLA) and certain genetic variants/genotypes in predicting the risk of these SCARs has been discussed in detail. The clinical presentation, diagnosis and management of drug-induced cutaneous reactions aim to stress pharmacovigilance in this regard, more so in those patients with multiple comorbidities or a recent alteration in their pharmacotherapy regimen.
CASE SERIES
Case 1
Phenytoin-associated TEN
A 3-year-old female child came with generalised erythematous maculopapular rashes with some vesicles and bullae, [Figure 1] with oral and perineal mucosal involvement and epithelial desquamation >10% body surface area. Perioral vesicles depicted in Figure 2. The lesions started on the back 4 days back and later progressed to the trunk, upper and lower limbs after intake of phenytoin (5 mg/kg/day) for mild traumatic brain injury associated with seizures and temporary loss of consciousness due to a fall 15 days before admission. Following the development of the above lesions, phenytoin was withdrawn. There were also reduced urine output and bilateral pedal oedema in the child. There was no previous history of allergic reactions/insect bites. She was not on any other concomitant medication at the time reaction started.

- Phenytoin-induced toxic epidermal necrolysis (Case 1) – Maculopapular rashes and vesicles over the back in a child with phenytoin-induced toxic epidermal necrolysis.

- Phenytoin-induced toxic epidermal necrolysis (Case 1) – Vesicles over perioral region and chin with ulceration over the lips.
On examination, the child had a positive pseudo-Nikolsky sign. She was diagnosed with phenytoin-associated toxic epidermal necrolysis. Laboratory investigation showed an absolute eosinophil count of 560/cu mm. There are no parasites in the peripheral smear. Liver and renal function parameters were normal. C-reactive protein (CRP) was elevated. Causality assessment was performed using the WHO-UMC scale and Naranjo algorithm. Causality using the WHO scale was certain, and by the Naranjo scale, it was probable causality.
She was started on intravenous fluids, warm saline gauze, ocular lubricants, systemic corticosteroids (prednisolone) and empirical antibiotics (azithromycin) for 10 days. The child was discharged after clinical improvement, a decrease in CRP levels and after ruling out signs of sepsis. She was advised to avoid phenytoin in the future and continue skin and eye care for 1 week and review.
Case 2
DRESS associated with sulfasalazine (SSZ)/aceclofenac
A 38-year-old female patient presented with raised itchy reddish lesions over the neck, scalp, face, trunk and bilateral upper and lower limbs, which were also associated with facial oedema. She was prescribed paracetamol, pantoprazole, metronidazole, doxycycline, plus Lactobacillus, along with fluid replacement therapy 1 week back for gastroenteritis, after which the lesions developed. She was on thyroxine supplementation for the past few years and was diagnosed with rheumatoid arthritis a few months back. She was started on SSZ and aceclofenac 2 weeks ago for rheumatoid arthritis. Laboratory investigations revealed a total leucocyte count of 19000/cu mm, 55% lymphocytes, 33% neutrophils, 3% eosinophils and 9% monocytes. The peripheral smear picture was of leucocytosis with lymphocytic predominance. Liver function tests (LFT) were elevated (aspartate transaminase - 129, alanine transaminase - 211 and alkaline phosphatase -171 U/L). Renal function tests were normal. Once the aceclofenac/SSZ combination was discontinued, her LFT values started to gradually reduce. Causality analysis done using the WHO scale was probable, and by the Naranjo scale, it was probable causality. She was diagnosed with DRESS syndrome associated with SSZ and aceclofenac. RegiSCAR scoring was performed for DRESS syndrome and found to be 2 (possible case).[6] She was managed with oral prednisolone and antihistaminics. She improved clinically with systemic corticosteroids and was discharged and advised to avoid the sulpha group of drugs and restrict the use of non-steroidal anti-inflammatory drug (NSAID) group of drugs in future.
Case 3
TEN secondary to oxcarbazepine
A 16-year-old female patient, known case of seizure disorder, was referred to our hospital with generalised reddish lesions for 4 days, which later progressed to blistering and epidermal desquamation of >10% body surface area. There was also swelling of the lips along with painful oral and genital lesions. Oral lesions were associated with dysphagia. She gives the history of starting oxcarbazepine 300 mg/day and clonazepam 0.5 mg at night, 1 week before, for epilepsy. Treatment history revealed that she had been taking syrup valproate for 6 years age of and was seizure free for almost 7 years after that, when she stopped taking it. Then was started on levetiracetam and clobazam at 13 years of age after an episode of seizure; however, her seizures were not fully controlled after a few months of treatment with the above drugs and hence switched over to oxcarbazepine 300 mg od and clonazepam 0.5 mg a week back, following which the lesions developed. There are no similar episodes in past and no history of drug allergy. Pseudo-Nikolsky sign was positive. Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) score (for assessing SCORTEN) was found to be one.[7] All laboratory reports were normal. She was diagnosed to have TEN associated with oxcarbazepine (clonazepam was found not to be the causative agent, as she had taken another benzodiazepine, clobazam, in the past without any reaction). Oxcarbazepine and clonazepam were withdrawn, following which the lesions started reducing. Causality using the WHO was certain, and using the Naranjo scale, it was determined to be probable. She was treated with cyclosporine with dexamethasone for 7 days and provided ophthalmological care. Oxcarbazepine was switched to levetiracetam and lacosamide, and she started improving clinically and was discharged with advice to avoid oxcarbazepine in the future for epilepsy.
Case 4
AGEP with angioedema secondary to phenytoin
A 53-year-old male patient came with complaints of multiple erythematous papules present all over the body, with a few coalescing to form plaques over the back, lower abdomen and bilateral upper limbs for 1 week, along with swelling of both eyelids for 3 days. There were also multiple pustules over the face, scalp, neck and trunk, and erythematous macules present over soles, palms and diffuse oedema over the bilateral eyelids and lips [Figures 3 and 4]. Dystrophy of both the great toenails was present. The patient was a case of traumatic brain injury, which happened 1 month ago, for which he was started on T. Phenytoin 100 mg Three times a day (TDS) and continued till the above lesions appeared. He was also a known diabetic for the past 8 years on metformin 500 mg bd. The patient was diagnosed with AGEP with angioedema secondary to phenytoin after performing a causality assessment. Causality assessment was determined to be certain by the WHO scale and probable by the Naranjo scale; thereafter, phenytoin was stopped. He was started on oral prednisolone and antihistamines, following which he improved clinically and was discharged.

- Acute generalised exanthematous pustulosis (AGEP) secondary to phenytoin (Case 4) – Patient with AGEP presenting with angioedema of the lips.

- Acute generalised exanthematous pustulosis (AGEP) secondary to phenytoin (Case 4) – Patient with AGEP presenting with multiple erythematous papules and plaques over the back.
Case 5
Amoxicillin/nimesulide-induced TEN
This 36-year-old female patient presented with fever and complaints of multiple dusky erythematous macules, hyperpigmented papules over bilateral lower limbs and targetoid lesions over trunk and a few vesicles present over bilateral upper limbs, which started appearing 2 days before presentation. Exfoliation was present over the palms. There was swelling of the lips and eyelids. Erosions with sloughing present over the lips, accompanied by painful oral lesions with dysphagia, were also seen. Congestion of eyes, purulent discharge with matting of eyelids for 1 day were also present. The patient had received Cap. Amoxyclav 625 mg twice daily (BD), T. Acetaminophen 500 mg Three times a day (TID), Nimesulide mouth dissolving tablets BD, T. Levocetirizine 5 mg at bedtime (HS) 1 week back for fever and myalgia, following which, she developed the symptoms mentioned above. There was no history of similar complaints or drug allergy in the past. Causality assessment of the ADRs was done. It was found to be probable by both the WHO-UMC scale and the Naranjo scale. Since the epithelial desquamation was more than 10%, she was diagnosed with amoxicillin/nimesulide-induced toxic epidermal necrolysis. SCORTEN score was 2.[7] Pseudo-Nikolsky sign was positive. CRP and procalcitonin were raised. She was managed with Cap. Cyclosporine, Inj. Dexamethasone and prophylactic antibiotics. Ocular care was given. As the patient showed signs of clinical improvement, she was discharged with oral corticosteroids and eye care.
DISCUSSION
Severe cutaneous adverse reactions (SCARs) constitute only a minority of CADRs, but due to the life-threatening nature of the reaction, they can require prompt identification to initiate treatment and undertake preventive measures.[3,8]
The case series presents a broad overview of the various drugs which may be associated with the occurrence of SCAR in a tertiary care hospital. Since all of the cases included here are serious ADRs, the time frame for reporting ADRs to the pharmacovigilance centre was within 3–5 days of the development of symptoms. The paediatric case with phenytoin-induced TEN was reported on the day of admission itself. The occurrence of a maculopapular rash/exanthems in patients on the above drugs/drug groups should prompt constant monitoring and follow-up of the patient to watch for worsening of the cutaneous symptoms, and if lesions progress to extensive blistering/desquamation, initiation of treatment with corticosteroids and other supportive therapy must be done immediately.
In the present case series, there were two cases of SJS/TEN (one each with phenytoin and oxcarbazepine) and one case of AGEP (phenytoin) associated with the use of antiepileptics. All the patients had taken the antiepileptic doses prescribed by the physicians. Serum drug levels of antiepileptics by therapeutic drug monitoring (TDM), HLA testing and testing for pharmacogenetic variants (e.g., CYP2C9 variants) were not done for any of these patients as these tests are not commonly available/accessible due to feasibility and cost issues. Being a drug with a narrow therapeutic index, TDM of phenytoin is helpful in avoiding many of the symptoms of phenytoin toxicity.[9] For patients on phenytoin, CYP2C9 genotyping was not done due to limited availability and restrictive costs of these genotyping kits.
Adverse reactions may be broadly of either type A, which are predictable reactions, based on properties of the drug and the drug action or type B, which are idiosyncratic and not predictable based on the pharmacology of the drug.[10] Hence, unlike the ‘on-target’ predictable ADRs, which are based on drug action, the off-target ADRs often have a wide variety of clinical presentations and underlying mechanisms.[11] The severe cutaneous adverse drug reactions (SCAR) are a type of T-cell mediated off-target CADRs which may often be life-threatening.[11]
There are several genetic and non-genetic factors associated with SCARs.[12] The presence of certain HLAs is associated with a higher risk of developing certain SCARs (including SJS/TEN and DRESS).[12] Similarly, some of the associated non-genetic factors associated with a higher risk of SCAR include age, gender, ethnicity, family history, concomitant drugs or diseases and certain viral/bacterial infections.[12] SJS/TEN has been reported at a higher rate in females, and although the number of cases is too small, a similar pattern was seen in our case series. A positive family history of SCAR was not present in any of the cases. History of certain viral infections such as coxsackie virus, parvovirus, human herpes virus and cytomegalovirus should also be noted in cases of DRESS and infections such as Mycoplasma pneumoniae, Chlamydia pneumoniae, Escherichia coli and parasitic infections are some of the triggering agents for AGEP.[12,13] Severe cases of SCAR, which do not respond to systemic corticosteroids, must be assessed for their viral load as well as antibody titres, as these infections can increase the risk of the occurrence of a drug rash.[12,13]
Similarly, in the case of anti-epileptic drugs (AED), the incidence of CADR with drugs such as phenytoin, carbamazepine and lamotrigine is associated with the starting dose of the AED, particularly with higher starting doses.[12] In the study, all the patients had received the AED dose recommended by the physicians, and the starting dose of AED in these patients was not high. The paediatric TEN case had a starting dose of 5 mg/kg/day of phenytoin; the AGEP patient was given a dose of phenytoin 100 mg TDS, and the oxcarbazepine-associated TEN patient had an oxcarbazepine starting dose of 300 mg OD.
A study by Chadwick et al. showed that higher serum concentrations of phenytoin were present at the time of development of early exanthematous drug reactions and recommend that therapy with phenytoin may be started at a lower dose and slowly titrated upwards to decrease the incidence of these eruptions and the same may be followed in case of anticonvulsant therapy with carbamazepine also.[14]
A meta-analysis of case–control studies has demonstrated a significant association between the presence of HLA-B*1502 and the development of phenytoin or lamotrigine-associated SJS-TEN.[15] Performing genetic testing for HLA-B 15*02 is recommended before initiating treatment with phenytoin, carbamazepine or oxcarbazepine, especially in patients of certain ancestry, as they may have a higher genetic risk.[16] The Clinical Pharmacogenetics Implementation Consortium (CPIC) 2014 guidelines recommend not using phenytoin as an anticonvulsant in patients who are positive for the HLA-B*15:02 allele.[17] Similarly, the CPIC 2018 guidelines recommend not to use carbamazepine or oxcarbazepine in patients positive for HLA-B*15:02 if they are naïve to treatment with carbamazepine or oxcarbazepine, as there is a greater risk of drug-induced SJS/TEN.[18] Another important factor associated with phenytoin-induced severe cutaneous adverse reactions (SCAR) includes genetic variants such as CYP2C9*3.[19] Dosage reduction in CYP2C9 intermediate metabolisers (CYP2C9*1/*3 and *1/*2) and poor metabolisers (CYP2C9*2/*3,*2/*2 and *3*3) should be considered at 25–50% of the recommended starting maintenance dose with further dose adjustment based on response and TDM.[17]
In the patient with SSZ-associated DRESS, the reaction started 2 weeks after the drug was started. A literature review of SSZ-associated DRESS describes the average time of onset of the condition to be between 10 and 60 days, with a median onset time of 28 days and also suggests that the pattern of organ involvement in DRESS varies with the offending drug, and SSZ-associated DRESS most often involves the liver.[20] A similar pattern was seen in our patient. The temporal association made it difficult to ascertain which drug (SSZ or aceclofenac) was the drug associated with DRESS. Neither of these drugs had been taken in the past before the current episode. Although diclofenac is one of the most commonly associated drugs with the development of DRESS syndrome [21] DRESS associated with aceclofenac, which is also a phenylacetic acid analgesic, has been reported in a few cases.[22,23] DRESS is an immune-mediated reaction and the proposed hypotheses for the development of DRESS include the following: Genetic susceptibility associated with some alleles of the HLA, accumulation of certain drug metabolites due to genetic deficiency of metabolising enzymes which stimulate an immune response in genetically susceptible individuals, development of antibodies against the offending drug causing immune response and reactivation of certain herpes group of viruses.[24,25]
There was one case of antibiotic/NSAID-associated TEN, i.e. associated with amoxicillin/nimesulide. The most common antibiotics associated with SJS/TEN in literature are beta lactams, sulphonamides and quinolones.[1,2]
The diagnosis should be based on clinical criteria such as RegiSCAR criteria for DRESS and EuroSCAR criteria for AGEP, with relevant laboratory tests such as skin biopsy, complete blood count, CRP, erythrocyte sedimentation rate, procalcitonin levels and viral serology.[12,13]
CONCLUSION
Once a SCAR is reported, the first and most important step is to identify the most likely offending agent for the SCAR and withdraw it. A detailed review of the medication history of the patient, history of prior/intercurrent viral/bacterial infections, previous allergy to same/similar drugs and any family history of drug allergies should be undertaken. Other common skin diseases which may resemble a CADR must be ruled out. The instrumental role of pharmacogenomics and personalised medicine in preventing life-threatening SCARs must be kept in mind while initiating treatment with certain antiepileptics.
Author’s contributions:
AS, VA, JVJ: Contributed to conceptualisation and designing of the study, acquisition of data and interpretation of data. All the authors contributed to drafting the article and revising it critically for important intellectual content, gave final approval of the version to be published, and all authors accept accountability for the work in ensuring accuracy or integrity of the work are appropriately investigated and resolved.
Ethical approval:
Ethical approval was obtained from Institutional Human Ethics Committee, Mahatma Gandhi Medical College and research Institute, Sri Balaji Vidyapeeth, Pondicherry, approval number MGMCRI/2024/04/IHEC/CS/50, dated 28th November 2024).
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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