Severe Cutaneous Adverse Reactions in a tertiary care hospital with perspectives on pharmacogenomics and personalised medicine

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.

Close

Figure 1:

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

Export to PPT

Close

Figure 2:

Phenytoin-induced toxic epidermal necrolysis (Case 1) – Vesicles over perioral region and chin with ulceration over the lips.

Export to PPT

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 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.

Close

Figure 3:

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

Export to PPT

Close

Figure 4:

Acute generalised exanthematous pustulosis (AGEP) secondary to phenytoin (Case 4) – Patient with AGEP presenting with multiple erythematous papules and plaques over the back.

Export to PPT

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.