|Year : 2021 | Volume
| Issue : 1 | Page : 24-28
A multicentric, prospective and retrospective analysis of Stevens–Johnson syndrome, toxic epidermal necrolysis and Stevens–Johnson syndrome/toxic epidermal necrolysis overlap: An Indian perspective
Ramesh Marne Bhat, Jyothi Jayaraman, Navyashree Suresha, Sukumar Dandekeri, Myfanwy Joanne D'souza
Department of Dermatology, Father Muller Medical College, Mangalore, Karnataka, India
|Date of Submission||14-Nov-2019|
|Date of Decision||18-Aug-2020|
|Date of Acceptance||11-Jan-2021|
|Date of Web Publication||25-Jun-2021|
Department of Dermatology, Father Muller Medical College, Mangalore - 575 002, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Stevens Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) represent adverse drug reactions characterized by generalized rash, blisters, epidermal detachment, mucosal and systemic involvement presenting as dermatological emergencies. Drugs are the most common culprits implicated in the pathogenesis of SJS /TEN. The primary step in the management of SJS/TEN is identification and stopping the offending drug. Materials and methods: This was a multi-centric retrospective as well as prospective observational study conducted in 7 tertiary care hospitals including Father Muller Medical College Hospital , Mangalore, India. A detailed evaluation of the hospital in patient record for 10 years retrospective from September 2015 and all new cases of SJS/TEN as well as SJS-TEN overlap presenting to these centres for 1 year prospective was performed. Detailed history was taken and clinical examination was recorded and different modalities of treatment was noted and compared. Results: A total of 152 patients with clinical diagnosis of SJS ,TEN and SJS-TEN overlap were analysed. Males were more commonly affected than females and history of drug intake was present in 118 patients (77.6%). The most common drugs which caused SJS/ TEN in our study were antibiotics in 40 patients (26.3%) followed by anti epileptics in 35 patients (23%) and nevirapine in 10 patients (6.5%). In our study the most common finding on cutaneous examination was maculopapular rash (19.3%). Conclusion: SJS and TEN form part of a spectrum of severe cutaneous drug reactions that can lead to high morbidity which can be reduced by early withdrawal of the offending drug and timely intervention. Individuals with known drug allergies need to be educated and drug allergy card has to be carried.
Keywords: Adverse drug reactions, antibiotics, Stevens–Johnson syndrome, toxic epidermal necrolysis
|How to cite this article:|
Bhat RM, Jayaraman J, Suresha N, Dandekeri S, D'souza MJ. A multicentric, prospective and retrospective analysis of Stevens–Johnson syndrome, toxic epidermal necrolysis and Stevens–Johnson syndrome/toxic epidermal necrolysis overlap: An Indian perspective. Indian J Drugs Dermatol 2021;7:24-8
|How to cite this URL:|
Bhat RM, Jayaraman J, Suresha N, Dandekeri S, D'souza MJ. A multicentric, prospective and retrospective analysis of Stevens–Johnson syndrome, toxic epidermal necrolysis and Stevens–Johnson syndrome/toxic epidermal necrolysis overlap: An Indian perspective. Indian J Drugs Dermatol [serial online] 2021 [cited 2021 Dec 2];7:24-8. Available from: https://www.ijdd.in/text.asp?2021/7/1/24/319359
| Introduction|| |
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) represent adverse drug reactions characterized by generalized rash, blisters and epidermal detachment and mucosal and systemic involvement presenting as dermatological emergencies. SJS and TEN share similar pathogenesis, but the classification is based on the degree of epithelial detachment.
The incidence of SJS is about 1.2–6 per million patient years and TEN 0.4 to 1.2 per million patient years. The mortality rate is three times higher in TEN when compared to SJS.,
Drugs are the most common culprits implicated in the pathogenesis of SJS/TEN, although these may occur secondary to infections and malignancies. The most common drugs seen in the literature search include anti-epileptics, antibiotics, anti-tuberculosis drugs, nonsteroidal anti-inflammatory drugs, allopurinol and cotrimoxazole.,, The prognosis of TEN is determined by using a score called SCORTEN. Daily evaluation of the score from day 1 may be helpful to determine the progression of disease to assess systemic involvement and mortality rate.
The primary step in the management of SJS/TEN is identification and stopping the offending drug. Other drugs mainly used in the management include oral steroids, cyclosporine, oral tacrolimus and cyclophosphamide. Intravenous immunoglobulin, plasmapheresis and use of biologics are found to be helpful in preventing systemic complications and reducing mortality.,,,
We undertook this research to study the incidence of SJS, TEN, SJS-TEN overlap cases, suspected drugs, associated morbidity and mortality among the patients in multiple centers across India.
| Methods|| |
This was a multicentric retrospective as well as prospective, observational study conducted in seven tertiary care hospitals including Father Muller Medical College Hospital, Mangalore, India, which had dermatology inpatient facility for handling emergency cases. These centers were chosen based on their applications to join the study and interest expressed by these on forum for IADVL academicians. Institutional Ethical Clearance was obtained. A detailed evaluation of the hospital in-patient record for 10 years retrospective from September 2015 and all new cases of SJS/TEN as well as SJS-TEN overlap presenting to these centers for 1-year prospective was performed.
The duration and extent of rash, drug intake, the time period between the drug intake and appearance of rash, systemic symptoms, the types of skin lesions, extent of epidermal detachment, mucosal involvement and systemic symptoms were recorded. The diagnosis of SJS/TEN and SJS-TEN overlap was made and drugs which had been taken within 4 weeks preceding the onset of symptoms were suspected as causative agents.
A detailed note of the type of treatment (systemic steroids, IvIg or others) was made in all prospective cases and where records were available for retrospective cases. The effect of various treatment modalities was recorded
The collected data were analyzed using frequency, percentage, standard deviation, mean, Chi-square test and Fisher's exact test. P < 0.05 was considered statistically significant. Statistical analysis was performed using the SPSS software version 23.
| Results|| |
A total of 152 patients with clinical diagnosis of SJS, TEN, and SJS-TEN overlap were analyzed. The most common age group involved was in the range of 31–40 years constituting 25% of the study population and P value was highly significant (P < 0.005). Males (90) outnumbered females (62) and history of drug intake was present in 118 patients (77.6%).
Clinical diagnosis of SJS, TEN, and SJS-TEN overlap was made based on history, clinical examination and hospital records available and total number of patients is depicted in [Table 1].
|Table 1: Number of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap|
Click here to view
The most common drugs which caused SJS/TEN in our study were antibiotics in 40 patients (26.3%) followed by anti-epileptics in 35 patients (23%) and nevirapine in 10 patients (6.5%).
Among antibiotics, quinolones were the most common accounting for 11% of cases and ofloxacin (3.9%) was the most common drug in the group. Cephalosporins in 15 patients (9.8%) were the other common causative antibiotic drugs.
Among antiepileptics, reactions were more common with phenytoin which was seen in 11.8% of patients followed by carbamazepine in 9.2%.
Reactions to less commonly reported drugs such as allopurinol was also observed in three patients (1.9%) [Table 2].
Ocular involvement was seen in 54 patients (35.5%), oral mucosa was involved in 89 patients (58.6%) and genital mucosa was involved in 29 patients (22.7%) [Figure 1] and [Figure 2].
One hundred and twenty-nine patients (84.9%) recovered after treatment, the most common modality of treatment used was systemic steroids in 81 patients (53.28%) and intravenous immunoglobulin in 3 patients. The different modalities of treatment used are depicted in [Table 3].
Four patients died during the course of the disease, out of which two were diagnosed with HIV and were on nevirapine. They developed TEN within 2 weeks of treatment and succumbed the disease.
Associated comorbidities were seen in 41 patients [Table 4]. Our study showed that advancing age, associated comorbidities and involvement of mucous membranes were associated with fatal outcome (P < 0.05).
In our study, the most common finding on cutaneous examination was maculopapular rash (19.3%) followed by target lesions (15.96%) [Figure 3] and [Figure 4]. A few rare presentations such as lichenoid rash (0.84%) and targetoid lesions (1.84%) were also noticed.
| Discussion|| |
Our study was conducted with an aim to assess the most common type of drug involved, duration of the disease, common treatment modalities and to study the outcome. Due to the high risk of mortality, the management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug along with specialized supportive care. Our study results were comparable to similar study conducted by Wang et al. which included retrospective analysis of 88 patients. The most common age group involved was in the range of 31–40 years; females were 48 in number (54.5%) and males were 40 (45.5%) where females outnumbered males.
A study conducted by Vora et al. enrolled 34 patients with cutaneous adverse drug reactions where 11–20 years constituted the majority of the study population. Hirapara et al. noted that out of 40 patients, 25 (62.5%) were male and 15 (37.5%) were female. A study conducted by Naveen et al. showed that among 22 patients, 14 (63.6%) were men and 8 were women (36.7%). Seventy eight patients (66.1%) in our study were classified into SJS. SJS/TEN overlap was seen in 11 patients (9.5%) and 27 (23.3%) patients with TEN.
Our study results were comparable to the study conducted by Wang et al. which showed among the 88 patients diagnosed, 54.5% had SJS, 38.6% with SJS/TEN overlap and 6.8% had TEN. Hirapara et al. found that in 40 included cases, 4 (10%), 15 (37.5%) and 21 (52.5%) cases were of SJS, SJS–TEN overlap, and TEN, respectively. In our study, antibiotics were the most common class of drugs observed to cause SJS/TEN followed by antiepileptics in about and Nevirapine in, respectively. Our study results were comparable to similar study conducted by Wang et al. which showed that among 88 patients diagnosed, antibiotics were found to be most common culprits in 24 patients (49%). Levofloxacin was the most common antibiotic where reactions were seen in three patients (6.1%) followed by traditional herbal medicines in seven cases (14.3%). Hirapara et al. showed that antimicrobials (27.1%) were the most commonly associated group of drugs followed by antivirals and nevirapine (23%). A retrospective study conducted by Devi et al. showed that anticonvulsants were the most commonly implicated drugs out of which a history of intake of carbamazepine was seen in 18 patients (46%). Naveen et al. showed that the most common drugs implicated were anti epileptics in 11 (50%) cases among which carbamazepine was the most common anti-epileptic used in 5 (40%) patients. Vora et al. found that in 34 patients with cutaneous adverse drug reactions, the most common drugs implicated were anti epileptics, out of which phenytoin was the most common in 74.4% patients followed by carbamazepine in 20.58%. Less reported drug such as allopurinol caused more severe reaction in three patients who were receiving the drug for the treatment of hyperuricemia in higher doses. Literature search revealed a high number of cases in Europe and Israel.
In our study, the most common finding on cutaneous examination was maculopapular rash (19.3%) followed by target lesions (15.96%). Less common presentations such as lichenoid rash (0.84%) and targetoid lesions (1.84%) were also noticed. Vora et al. also found that maculopapular rash was the most common presentation seen in 58.8% of patients which was similar to our study. Ocular involvement was seen in about 54 patients (35.5%), oral cavity involvement in 89 patients (58.6%) and genital mucosa in 29 patients (22.7%).
In our study, out of 152 patients, 81 (53.28%) were treated with oral and injectable steroids showed good improvement and 129 (84.9%) of patients recovered without any sequelae which was comparable with a study conducted by Devi et al. and showed that out of 41 patients, 33 (81%) recovered completely.
Four patients died during the course of the disease out of which two were on nevirapine succumbed to death within 2 weeks of onset of symptoms probably because of immunosuppression and other opportunistic infections.
| Conclusion|| |
SJS and TEN form the part of a spectrum of severe cutaneous drug reactions that can lead to high morbidity which can be reduced by early withdrawal of the offending drug and timely intervention with medications and multispecialty referrals.
The importance of meticulous adverse drug reaction data entry and monitoring cannot be undermined. Individuals with known drug allergies need to be educated regarding the importance of carrying a drug allergy card in person and avoidance of over-the-counter medications
The main limitation of our study is data on mortality was available from only two centres and data, prognosis with respect to various treatment modalities were incomplete in certain cases.
IADVL Research grant.
BVVSS Nijalingappa Medical College, HSK Hospital and Research Centre, Bagalkot – Dr Mahajabeen Madarkar. Eastern Command Medical College, Kolkatta- Dr Manas Chatterjee. JSS Medical College , Mysore – Dr Ashwini PK. Kasturba Medical College, Manipal- Dr Shricharith Shetty. Kasturba Medical College, Mangalore – Dr Deepthi Dsouza, Dr Pramod Kumar. Pondicherry Institute of Medical Sciences, Pondicherry – Dr Satyaki Ganguly.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Yamane Y, Matsukura S, Watanabe Y, Yamaguchi Y, Nakamura K, Kambara T, et al
. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients – Treatment and outcome. Allergol Int 2016;65:74-81.
Law EH, Leung M. Corticosteroids in Stevens Johnson Syndrome/ toxic epidermal necrolysis: Current evidence and implications for future research. Ann Pharmacother 2015;49:335-42.
Sanmarkan AD, Sori T, Thappa DM, Jaisankar TJ. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis over a period of 10 years. Indian J Dermatol 2011;56:25-9.
] [Full text]
Sharma VK, Sethuraman G, Minz A. Stevens Johnson syndrome, toxic epidermal necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome. Indian J Dermatol Venereol Leprol 2008;74:238-40.
] [Full text]
Bastuji Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92-6.
Pawar MP, Pore SM, Pradhan SN, Burute SR, Bhoi UY, Ramanand SJ, et al
. Nevirapine: Most common cause of cutaneous adverse drug reactions in an outpatient department of a teritiary care hospital. J Clin Diagn Res 2015;9:FC17-20.
Rajput R, Sagari S, Durgavanshi A, Kanwar A. Paracetamol induced Steven-Johnson syndrome: A rare case report. Contemp Clin Dent 2015;6:S278-81.
Patel TK, Barvaliya MJ, Sharma D, Tripathi C. A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol 2013;79:389-98.
] [Full text]
Oliveira A, Sanches M, Selores M. Stevens-Johnson syndrome and toxic epidermal necrolysis. Acta Med Port 2011;24 Suppl 4:995-1002.
Fujita Y, Yoshioka N, Abe R, Murata J, Hoshina D, Mae H, et al
. Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens-Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol 2011;65:65-8.
Bansal S, Garg VK, Sardana K, Sarkar R. A clinicotherapeutic analysis of Stevens Johnson syndrome and toxic epidermal necrolysis with an emphasis on the predictive value and accuracy of SCORe of Toxic Epidermal Necrolysis. Int J Dermatol 2015;54:e18-26.
Garcia Doval I, Lecleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Steven Johnsons syndrome: Does early withdrawl of causative drugs decrease the risk of death? Arch Dermatol 2000;136:323-7.
Fernando SL. The management of toxic epidermal necrolysis. Australas J Dermatol 2012;53:165-71.
Wang L, Mei XL. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 88 Chinese patients. Chin Med J (Engl) 2017;130:1062 8.
Vora R, Diwan N, Jivani N, Singhal R. A study of adverse cutaneous drug reactions (ACDR) owing to antiepileptics at a rural-based tertiarycare center, Gujarat. Natl J Physiol Pharm Pharmacol 2016;6:140-5.
Hirapara HN, Patel TK, Barvaliya MJ, Tripathi C. Drug-induced Stevens-Johnson syndrome in Indian population: A multicentric retrospective analysis. Niger J Clin Pract 2017;20:978-83.
] [Full text]
Naveen KN, Pai VV, Rai V, Athanikar SB. Retrospective analysis of Steven Johnson syndrome and toxic epidermal necrolysis over a period of 5 years from northern Karnataka, India. Indian J Pharmacol 2013;45:80-2.
] [Full text]
Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine – The commonest cause of toxic epidermal necrolysis and Stevens-Johnson syndrome: A study of 7 years. Indian J Dermatol Venereol Leprol 2005;71:325-8.
] [Full text]
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]