Stevens–Johnson syndrome: An adverse drug reaction with various drugs

INTRODUCTION

Hospital admissions are a common consequence of adverse drug reactions (ADRs) in both tertiary health and primary health care centre. ADRs not only impact the patients’ quality of life but they are also creating an increased burden on the healthcare system. They have led to increased morbidity and mortality and are posing to be a significant public health issue.^[1] According to a report in Europe, 3.6% of patients were admitted due to ADRs, and a further 10% of patients developed side effects during their hospital stay.^[2] Amongst all the reactions, skin disorders are the most common ADRs that we see in our medical career. Amongst the various ADRs, cutaneous drug reactions are the most common. The most serious type of mucocutaneous ADR is Stevens–Johnson Syndrome (SJS), which is a rare and potentially fatal type of cutaneous reaction and presents a high risk to the patient.^[3] According to the global data, the mortality rate for SJS ranges from 15% to 29%.^[4]

SJS is a type of Serious Cutaneous Adverse Reaction disorder characterised by mucocutaneous tenderness, haemorrhagic erosions, erythema, and epidermal detachment presenting as blisters and areas of denuded skin.^[5] The clinical features include erythema, blisters, skin and mucous membrane pain, epidermal exfoliation, and characteristic skin lesions, which involve the eyes and/or oral cavity. Multisystem damage may occur in some cases. SJS is classified according to the involvement of the epidermolysis area and is characterised by <10% of body surface area (BSA).^[6]

The aetiology behind SJS is not very clear, but the likely mechanism is due to a Type IV hypersensitivity-mediated, immune-mediated.^[7] According to a literature review from India, the most common factor responsible for SJS was drug induced, which accounted for 97% of all cases. A report shows that at 37%, antibiotics are the most frequent class of drug responsible for drug-induced SJS, followed by anti-epileptics (35%) and non-steroidal anti-inflammatory drugs (16%). The most common drugs comprised carbamazepine (18%) followed by phenytoin (13%), fluoroquinolones (8%), and paracetamol and sulphonamides (6%) each.^[8] In addition to this, drugs such as allopurinol, anti-epileptic drugs, sulphonamides, antibiotics, and antiretroviral drugs have also been identified to be responsible for SJS.^[9]

This case series highlights various drugs that are responsible for drug-induced SJS.

MATERIALS AND METHODS

This study was conducted at the ADR Monitoring Centre (AMC) of the Pharmacovigilance Programme of India, Christian Medical College and Hospital, Ludhiana. A total of 10 diagnosed cases were collected from various departments at Christian Medical College and Hospital, Ludhiana, from July 2022 to July 2023. The causality assessment was done by applying the Naranjo causality scale assessment. The ADR Probability Scale was developed in 1991 by Naranjo. It consists of a series of 10 questions with responses of “yes,” “no,” and “don’t know,” where different point values (−1, 0, +1 or +2) are assigned to each answer. The reaction is deemed definite if the score is 9 or above, probable if it is 5–8, possible if it is 1–4, and doubtful if it is 0 or lower. The total scores range from −4 to +13.^[10]

RESULTS

A total of 10 cases of SJS were collected from various departments of Christian Medical College and hospital within 1 year. Table 1 shows the detailed comprehensive patient review, and Figure 1 shows individual drugs that caused SJS in patients.

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Figure 1:

Percentage distribution of different drugs leading to Stevens–Johnson syndrome (n=10).

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DISCUSSION

The World Health Organization defines ADR’s as “a response to a medication that is noxious and unintended and occurs at doses normally used in man.”^[11] SJS is a rare autoimmune disease characterised by the involvement of skin and mucosal membranes, which is accompanied by high-grade fever, blistering exanthema of macules, and atypical target-like lesions.^[3] In Australia, a retrospective study was done to ascertain the mortality rate, and the mortality rate was observed to be 17%.^[12] Another study conducted in India reported the mortality rate to be 17.6% which is by the global trends.^[13]

The management of SJS includes immediate cessation of the suspect product, followed by symptomatic management, which includes maintenance of airway, breathing, and circulation. The drug therapy includes cyclosporine, corticosteroids, intravenous immunoglobulin, and TNF-α inhibitors.^[14] It has been observed that SJS occurs within 2 months of drug initiation in more than 90% of the cases.^[7] We have presented a case series where the drugs responsible for SJS include doxycycline, fluconazole, cefixime, phenytoin, piperacillin-tazobactam, sulfadiazine, oxcarbazepine, and ceftriaxone. Hence, antimicrobials (AMAs) represent 70% of the total cases of SJS, followed by anti-epileptics (30%).

Amongst AMAs, cephalosporins are mostly responsible for the occurrence of SJS. Cefixime, a third-generation cephalosporin, has rarely been associated with SJS.^[14] Doxycycline, a class of tetracycline, has also been connected to the occurrence of SJS when used in ophthalmological disorders.^[15] A few cases of SJS with the combination of piperacillin and tazobactam, which belongs to the beta-lactam group of AMAs, have also been observed.^[16] In a literature review on fluconazole, an anti-fungal drug, it has also been implicated in an increasing number of SJS cases.^[17]

Oxcarbazepine is an anticonvulsant that is structurally similar to carbamazepine. A review of literature suggested that oxcarbazepine-induced SJS has rarely been reported.^[18]

In this case, one patient died because of multi-organ failure, which is a manifestation of SJS. The risk factors associated with mortality include age over 40 years, the existence of a related cancer, BSA involvement >10%, serum bicarbonate concentration <20 mmol/L, serum urea nitrogen >10 mmol/L, serum glucose >14 mmol/L, heart rate >120 beats per minute and chronic renal disease.^[19]

The clinical manifestations of SJS are characterised by a rash that starts from the macula and develops into papules and urticarial lesions, which are not pruritic. Early symptom detection, addressing or eliminating the underlying causes and offering appropriate supportive therapy are all critical to the effectiveness of SJS treatment. The treatment focuses on symptomatic management such as protecting the exposed viable dermis, lowering the danger of infection, minimising the risk of pigmentation alterations and scarring and maximising re-epithelialisation, which are guiding principles of wound care. Facilitating the healing process can lower the risk of septicaemia and skin infections, which can be the cause of patient death.^[20]

Withdrawing the suspect drug causing SJS is of utmost importance. The most common drugs utilised are a combination of corticosteroids and intravenous immunoglobulins. Other drugs which can be used include cyclosporine A and TNF-α inhibitors. Plasmapheresis is also used, which involves the removal of the suspect drug.^[21]

Therefore, the reporting of SJS cases is essential to increase awareness amongst healthcare workers. In addition to this, identification of the suspect product and its withdrawal is often the first step in the management of SJS. Therefore, this case series was put together to help describe the ADRs, especially SJS, with these medications and to help raise awareness.

CONCLUSION

In this case series, 70% of SJS were due to the use of antibiotics, mostly cephalosporins and 30% of cases had SJS due to anti-epileptics. One of the patients died due to SJS, which was considered a fatal incident. Few studies have proven to have 15– 29% of mortality with SJS, and in our case series, it showed 10% mortality. Moreover, all the cases had a probable association with the suspect drugs, which was ascertained after applying the Naranjo causality assessment scale. This case study has highlighted the drugs responsible for causing SJS, and more such cases can be reported through active surveillance.