Rapid review of drug induced Stevens Johnson Syndrome case reports from 2003 to 2023: Trends among monoclonal antibodies and systemic immunosuppressant therapy

Abstract

Background

Drug-induced Steven-Johnson Syndrome (SJS) is a life-threatening hypersensitivity reaction and systemic steroid immunosuppressant therapy is not universally recommended. With the changing landscape of new drugs, it is important to determine emerging trends in this severe drug induced adverse event.

Objective

The objectives were to examine drug induced SJS case reports published from January 1 2003 to December 31 2023 for emerging trends of drugs implicated and systemic immunosuppressant therapy administered.

Methods

Literature search was done using PubMed (MEDLINE) database with keywords and Boolean terms, “Stevens Johnson Syndrome” AND “Case Report,” filtered for the time period of interest, articles available free and in English. Included case reports were only studies in which a single drug was implicated.

Results

Forty-nine case reports met inclusion criteria and critical analysis of quality rated studies from moderate to strong; however, causality assessment instrument was only reported for 10 (20%) case reports. There was equal distribution by sex; patient ages ranged from 2 to 95 years and 34 (69.4%) case reports originated from countries of the Asian continent. Most common drug implicated was carbamazepine, 5 (10.2%); pembrolizumab was implicated in 4 of 9 case reports involving monoclonal antibody drugs. Thirty-seven patients (75.5%) received systemic steroid immunosuppressant therapy. Two patients (4.1%) died during the clinical course.

Conclusion

The published case reports are predominately from countries known to be at higher risk of drug induced SJS and the emerging greater number of case reports implicating pembrolizumab may be an important safety concern, needing further investigation. Systemic steroid use was the preferred immunosuppressant therapy.

Keywords

drug induced Stevens Johnson Syndrome monoclonal antibodies pembrolizumab

Introduction

Steven-Johnson Syndrome (SJS) is a life-threatening type IV hypersensitivity reaction of the skin and mucous membranes and is reported to be a rare drug induced adverse event which requires an immediate withdrawal of the associated drug.^1,2 Historically, systemic steroid administration is a treatment option for immunosuppression; however, there is limited evidence of clinical benefits.^3–6

In a systematic review of published case reports between 1980 and 2020, phenytoin, carbamazepine, lamotrigine and allopurinol were implicated in 3 to 5% of the drug induced SJS cases identified.⁷ These small molecule drugs are also in the 2004-2021 list of top drugs associated with SJS individual case safety reports of the Food and Drug Administration Adverse Event Reporting System (FAERS).⁸ Also included on the list of the FAERS are large molecule drugs, such as monoclonal antibodies. It is important to explore other sources of case reports for changes in common drugs implicated in SJS, especially with the expanding market of monoclonal antibodies.⁹ Therefore, the primary purpose of this rapid review study was to describe the drugs implicated in published drug induced SJS case reports from January 1 2003 to December 31 2023. Furthermore, with the limited evidence supporting the use of systemic steroid immunosuppressant therapy, the study will explore trends in the use of systemic immunosuppressant therapy as a secondary purpose. The objectives of the study were to examine drug induced SJS case reports for emerging trends of drugs implicated and systemic immunosuppressant therapy administered.

Methodology

A rapid review search strategy was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for rapid reviews.¹⁰ Literature search was done on May 28, 2024 using PubMed/MEDLINE database; the search was restricted to this database to ensure only case reports from peered review journals were included. Included keywords with Boolean terms were “Stevens Johnson Syndrome” AND “Case report.” The search was filtered to only include journal articles, written in English, free full text available and published between January 1, 2003 and December 31, 2023. Language and free access availability restrictions were determined by the absence of funding support for this study. No ethical approval was required for this study because it was based on secondary analysis of data obtained from peer reviewed published literature. Google Sheets on Google Documents Share Platform was used to organize and manage the yielded citations for the title/abstract screening, full paper inclusion and the data extraction phases. At least two members of the student team (GM, RC, KG, SD, and DG) independently screened title and abstract of the identified records for inclusion/exclusion; where there was disagreement, consensus was resolved by MGW. Inclusion criteria for this study were articles that involved a single case report of a patient confirmed with only drug induced SJS (with or without diagnostic confirmatory tests) and implicating a single drug. Case reports of toxic epidermal necrolysis, which represents a greater severity of SJS and erythema multiforme which may be considered as a part of the spectrum of severity, although distinct differences in the associated lesions exist¹ were excluded. Review articles and editorials were also excluded. Initial screening of record required inclusion of the term SJS in either the title or abstract; articles without abstract were passed directly to full paper review phase. Articles shortlisted for full paper review were assessed to confirm inclusion/exclusion criteria were satisfied. Articles meeting inclusion criteria were then passed to the data extraction phase.

Data extraction and quality assessment

A data extraction spreadsheet was designed using Google Sheets on the Google Documents Share Platform. Quality assessment was done using a modification of the checklist endorsed by the International Society of Pharmacovigilance (ISoP) and International Society of Pharmacoepidemiology (ISPE)¹¹ and further developed into a quantifiable instrument by experts from both societies.¹² The original instrument consists of 18 items defined as required for publication of adverse events related to drugs.¹¹ The items measure the adverse events in three domains: 5 items in drug information and therapeutic regimen; 8 items on patient history, diagnosis and medications; and 5 items of details of adverse event. Items present in the publication were quantified as follows: 0 point for ‘no’ if item was absent from the case report, 1 point for ‘unclear’ if inadequately reported and 2 points for ‘yes’ when adequately reported. For this study, the modified instrument included only the items experts identified during the instrument validation process as present in at least 90% of case reports and the use of a causality assessment instrument. Examples of causality assessment instruments include the Naranjo Scale, the World Health Organization-Uppsala Monitoring Center (WHO-UMC) System and the algorithm of drug causality for epidermal necrolysis (ALDEN). Although response to dechallenge/rechallenge is required information for some causality assessments, these were considered unrealistic expectation of drug induced SJS because the severity of this disorder requires immediate withdrawal of the offending drug and unlikely re-challenge consideration.¹³ In total, 12 items were included in this modified instrument (Table 1). Additional information extracted from the articles were drug name, country from which the case report originated, patient age and sex, time of onset of SJS from first dosing of implicated drug, type of causality assessment instrument used, the systemic immunosuppressant drugs administered to treat SJS and patient mortality outcomes (survival or death, time to event, cause of death). Data extraction was restricted to two members of the team (RC and GM) who initially worked independently; discrepancies were reviewed collectively and resolved through discussion with MGW.

Table 1.

Modified Quality Assessment Instrument for drug-induced case reports for adverse events (AEs).

Item 1: Drug name reported

Item 2: Daily dose and dosing regimen reported

Item 3: Route of administration reported

Item 4: Length of treatment period/time of onset of AE reported

Item 5: Age reported

Item 6: Sex reported

Item 7: The diagnosis for which the implicated drug was administered was stated

Item 8: Are concurrent diseases analysed/considered with regards to their relevance to the AE*

Item 9: The involvement of concomitant medications with AE was considered/discussed in the report*

Item 10: The AE/interaction described

Item 11: How the AE was diagnosed using appropriate diagnostic tests (including lab tests) reported.

Item 12: There is a description of the algorithm/instrument/scale used for causality assessment*

* Items required of case reports of AE; but reported in less than 90% of case reports of pilot test¹²; scoring instructions modified from a previous publication¹⁴; for each item presented in case report, 0 points for ‘no’ if it was not reported in the case report, 1 point for ‘unclear’ if inadequately reported and 2 points for ‘yes’ when adequately reported. For each case report the average score (out of 12) is calculated. Based on a maximum quality rating score of 2, studies assigned a quality rating of weak = 0-0.50, moderate = 0.51-1.50 or strong = 1.51-2.00.

Data analysis

Descriptive statistical analysis using IBM SPSS Statistics 25 involved the use of means, medians, minimum to maximum values and interquartile range for continuous variables and proportions for categorical variables. The quality rating of each included article was categorically defined as previously described,¹⁴ which required summing the scores for each item and dividing by the total number of items in instrument (n = 12). Based on the maximum quality rating score of 2, studies were then categorically assigned a quality rating of weak (score of 0 to 0.50), moderate (score of 0.51 to 1.50) or strong (score of 1.51 to 2.00).

Results

The process of the strategic search and review is depicted in Figure 1 (PRISMA flowchart adapted from Page et al.).¹⁵ A total of 530 citations were retrieved when restricted to the years of interest once filtered for available free and only English, 218 citations remained for examination of title and abstract. The title/abstract screening yielded 129 citations for full paper assessment. Assessment of full articles resulted in the exclusion of 80 citations; reasons for exclusion included more than one drug implicated to be related to SJS; the article reported more than one patient; patient was diagnosed with mixed cutaneous adverse events. Forty-nine case reports met the inclusion criteria for this review.

Figure 1.

PRISMA flow chart; adopted from Page et al.¹⁵

Quality assessment

In terms of publication trends for the 20 years reviewed, cases matching the inclusion criteria were published between 2004 and 2023. Table 2 shows quality assessment using the modified ISoP/ISPE assessment instrument for case report of adverse drug reaction. Along with names of the drug implicated, all articles reported patient’s sex, age and description of the adverse event. Indication for drug administration was clearly described in 46 (94%) case reports; but only 34, (69%) provided information on daily dose/dosing regimen and only 19 (39%) provided information on the route of administration. Forty two case reports (86 %) clearly described how SJS was diagnosed; time of onset of SJS from dose initiation was clearly reported in 44 (90%) case reports. Use of a causality analysis instrument was provided in 10 (20%) case reports. Consideration of comorbidity involvement in the adverse event was discussed in 7 (14%) case reports and co-administered drug consideration in 6 (12%) case reports. Quality rating ranged from 0.83 to 1.83 (median = 1.33; interquartile range = 0.25) with 40 (82%) case reports ranked as moderate. The other 9 (18%) case reports were ranked as strong and all published between 2015 and 2023.

Table 2.

Quality Assessment of included case reports using the 12 items listed in the Modified Quality Assessment Instrument (see Table 1).

Quality rating	Item 1	Item 2	Item 3	Item 4	Item 5	Item 6	Item 7	Item 8	Item 9	Item 10	Item 11	Item 12
Strong [1.58-1.83]
Anis TR et al. 2023¹⁶	Y	Y	Y	Y	Y	Y	U	N	N	Y	Y	Y
Aroke D et al. 2017¹⁷	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N
Deng M et al. 2021¹⁸	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	Y
Jawaro T et al. 2018¹⁹	Y	Y	Y	Y	Y	Y	Y	N	N	Y	Y	Y
Paik S et al. 2015²⁰	Y	Y	N	Y	Y	Y	Y	N	Y	Y	Y	Y
Shakya P et al. 2021²¹	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	N
Srinivasan S et al. 2019²²	Y	Y	Y	Y	Y	Y	Y	N	N	Y	Y	Y
Tran HT et al. 2021²³	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	N
Venkateswaran N et al. 2020²⁴	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	N
Moderate [0.83-1.50]
Akıncı B et al. 2017²⁵	Y	Y	N	U	Y	Y	Y	N	N	Y	Y	N
Al-Barzinji N et al. 2023²⁶	Y	Y	Y	Y	Y	Y	Y	N	N	Y	U	N
Alsulami S et al. 2023²⁷	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Bae H et al. 2013²⁸	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Bainstrument S et al. 2022²⁹	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	Y
Beken B et al. 2017³⁰	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Cao J et al. 2021³¹	Y	Y	N	Y	Y	Y	Y	N	N	Y	U	N
Castana O et al. 2009³²	Y	N	Y	N	Y	Y	Y	N	N	Y	Y	N
Chirasuthat P et al. 2018³³	Y	N	N	Y	Y	Y	Y	N	N	Y	Y	N
Cravens MG et al. 2019³⁴	Y	N	N	Y	Y	Y	Y	N	N	Y	Y	N
Das JK et al. 2011³⁵	Y	Y	Y	Y	Y	Y	Y	N	N	Y	N	N
Davoodi L et al. 2020³⁶	Y	Y	N	Y	Y	Y	Y	Y	N	Y	Y	N
Diep D et al. 2022³⁷	Y	N	N	U	Y	Y	Y	N	N	Y	Y	N
Gracia-Cazaña T et al. 2021³⁸	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Gui MZ et al. 2021³⁹	Y	N	Y	Y	Y	Y	N	N	N	Y	Y	Y
Hiraki A et al. 2004⁴⁰	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Kandil AO et al. 2010⁴¹	Y	N	N	Y	Y	Y	Y	N	N	Y	Y	N
Khan AA et al. 2022⁴²	Y	Y	Y	Y	Y	Y	N	N	N	Y	Y	N
Khor AH et al. 2016⁴³	Y	Y	N	Y	Y	Y	Y	N	Y	Y	N	Y
Kurian CJ et al. 2022⁴⁴	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Li X et al. 2023⁴⁵	Y	N	N	Y	Y	Y	Y	N	N	Y	Y	N
Lin LC et al. 2009⁴⁶	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
López-Gómez V et al. 2019⁴⁷	Y	N	N	Y	Y	Y	Y	U	N	Y	Y	N
Machida M et al. 2022⁴⁸	Y	Y	N	Y	Y	Y	Y	Y	N	Y	N	N
Mishra M et al. 2019⁴⁹	Y	N	N	Y	Y	Y	Y	N	N	Y	N	N
Mkhoyan A et al. 2023⁵⁰	Y	N	Y	Y	Y	Y	Y	N	N	Y	Y	Y
Nakamura R et al. 2022⁵¹	Y	N	N	Y	Y	Y	Y	Y	Y	Y	Y	N
Paik S et al. 2015⁵²	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	Y
Rajput R et al. 2015⁵³	Y	N	Y	U	Y	Y	Y	N	N	Y	Y	N
Salama M. 2009⁵⁴	Y	Y	Y	Y	Y	Y	Y	N	N	Y	Y	N
Sandhu M et al. 2023⁵⁵	Y	Y	Y	Y	Y	Y	Y	N	N	Y	Y	N
Shabrawishi M et al. 2019⁵⁶	Y	N	N	N	Y	Y	Y	N	N	Y	N	N
Sharma SR et al. 2011⁵⁷	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Shaw B et al. 2023⁵⁸	Y	N	Y	Y	Y	Y	Y	Y	N	Y	Y	N
Shetty SR et al. 2010⁵⁹	Y	Y	Y	Y	Y	Y	Y	N	N	Y	Y	N
Shrestha AB et al. 2022⁶⁰	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Wu JY et al. 2022⁶¹	Y	N	N	Y	Y	Y	Y	N	N	Y	Y	N
Wu MK et al. 2015⁶²	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
Xu L et al. 2018⁶³	Y	Y	Y	Y	Y	Y	Y	N	N	Y	Y	N
Yasui-Furukori N et al. 2014⁶⁴	Y	Y	N	Y	Y	Y	Y	N	N	Y	Y	N
% Yes	100	69	41	90	100	100	94	14	14	100	86	20

Abbreviations: Y-Yes; U-Unclear; N-No.

Tables 3 and 4 present the extracted information of the included case reports grouped by the large (9 case reports) and small (40 case reports) molecule drug type, respectively. In terms of country distribution, 34 (69.4%) of the studies involved patients located on the continent of Asia: 8 from India,^{20,22,35,49,52,53,57,59} 6 from China,^{18,31,39,45,61,63} 4 from Japan,^40,48,51,64 2 case reports each from Taiwan,^46,62 Turkey,^25,30 and Pakistan,^29,42 one case report each from Armenia,⁵⁴ Bangladesh,⁶⁰ Iran,³⁶ Iraq,²⁶ Korea,²⁸ Malaysia,⁴³ Nepal,²¹ Saudi Arabia,²⁷ Thailand,³³ and Vietnam.²³ Ten case reports originated from the United States of America,^{16,19,24,34,37,44,55,56,58,65} 2 case reports each from Spain,^38,47 and one case report each from Australia,⁵⁴ Cameroon,¹⁷ and Greece.³² There was no difference in distribution of the case reports by sex; 26 (53%) males versus 23 (47%) females (chi-square analysis, p = 0.67). Ages ranged from 2 to 95 years (median = 40 years) with 8 (16%) case reports involving paediatric patients (<18 years)^{21,25,30,39,46,51,53,63} and 14 (29%) were ageing patients (>60 years).^{16,18,22,24,28,31,33,38,43,45,47,48,55,61} The 49 case reports involved 35 different drugs of which 6 were large molecule drugs, specifically monoclonal antibody drugs and 29 were small molecule drugs. The most common drugs implicated were carbamazepine with 5 (10.2%) case reports,^{23,28,29,37,43} pembrolizumab with 4 (8.2%) case reports,^31,48,55,61 and 3 (6.1%) case reports each for azithromycin,^27,49,63 and oxcarbazepine.^30,46,57

Table 3.

Large Molecule Drugs (9 case reports).

Drug	First Author (Yr)Country	Sex/age	Time of onset of SJS from dosing	Type of causality analysis done/score	Systemic immunosuppressant/patient outcome (survived or died with time to death
Adalimumab	Salama M. (2009)⁵⁴ Australia	Male/29	16 weeks	-	Hydrocortisone, prednisone/survived
Atezolizumab	Chirasuthat P (2018)³³ Thailand	Male/75	2 days	-	Dexamethasone, prednisolone/survived
Nivolumab	Gracia-Cazaña T. (2021)³⁸ Spain	Male/78	4 weeks	-	Methylprednisolone, prednisone/survived
Pembrolizumab	Cao J (2021)³¹ China	Male/69	2 weeks	-	Methylprednisolone, immunoglobulin/survived
	Machida M (2022)⁴⁸/Japan	Male/68	21 days	-	Prednisolone/survived
	Sandhu M. (2023)⁵⁵USA	Female/75	14 days	-	Methylprednisolone, prednisone/survived
	Wu JY. (2022)⁶¹China	Female/68	20 days	-	Methylprednisolone, gamma globulin/survived
Sintilimab	Li X (2023)⁴⁵China	Male/76	9 weeks	-	Methylprednisolone, immunoglobulin/survived
Tocilizumab	Venkateswaran N. (2020)²⁴USA	Female/82	1 month	-	Steroids (names not specified), gamma globulin/survived

Abbreviations: USA-United States of America. All case reports involved monoclonal antibodies.

Table 4.

Small molecule drugs (40 case reports).

Drug	First Author (Yr)Country	Sex/Age	Time of onset of SJS from dosing	Type of causality analysis done/score	Systemic immunosuppressant/patient outcome (survived or died with time to death
Acetaminophen	Nakamura R (2022)⁵¹Japan	Male/6	1 day	-	Methylprednisolone, immunoglobulin, cyclosporine/died on day 90
	Rajput R (2015)⁵³India	Male/14	Unclear	-	Prednisolone/survived
Allopurinol	Anis TR (2023)¹⁶USA	Female/95	10 days	Naranjo Scale-Probable	Methylprednisolone/survived
	Paik S (2015b)⁵²India	Female/43	10 days	ALDEN-Very Probable	Dexamethasone/survived
Amoxicillin	Srinivasan S. (2019)²²India	Male/63	12 h	Naranjo Scale-ProbableWHO-UMC System-Probable/Likely	Prednisolone/survived
Alpelisib	Kurian CJ (2022)⁴⁴USA	Female/60	19 days	-	Methylprednisolone, prednisone/survived
Azithromycin	Alsulami S (2023)²⁷Saudi Arabia	Female/28	6 days	-	Hydrocortisone, prednisone/survived
	Mishra M (2019)⁴⁹India	Female/18	2 months	-	None/survived
	Xu L (2018)⁶³China	Male/6	2 days	-	Dexamethasone/survived
Carbamazepine	Bae HM. (2013)²⁸Korea	Male/68	4 days	-	Prednisolone/survived
	Bainstrument S. (2022)²⁹Pakistan	Male/36	2 weeks	Naranjo Scale-Possible	Hydrocortisone/survived
	Diep D. (2022)³⁷USA	Female/25	Unclear	-	Prednisolone/survived
	Khor AH. (2016)⁴³Malaysia	Female/63	14 days	ALDEN-Very probable	None/survived
	Tran HT (2021)²³Vietnam	Male/21	20 days	-	None/survived
Cefixime	Shrestha AB. (2022)⁶⁰Bangladesh	Male/40	6 Days	-	Prednisolone/survived
Ceftriaxone	Mkhoyan A (2023)⁵⁰Armenia	Female/55	2 days	Naranjo Scale-Probable	Prednisolone/survived
Cefuroxime	Shabrawishi M. (2019)⁵⁶USA	Female/41	Unclear	-	Steroids (name not specified), azathioprine, cyclosporine/survived
Ciprofloxacin	Cravens MG (2019)³⁴USA	Male/49	2 days	-	None/survived
Chlordiazepoxide	Jawaro T. (2018)¹⁹USA	Female/29	2 days	Naranjo Scale-ProbableALDEN Scale-Probable	None/survived
Chloroquine	Das JK (2011)³⁵India	Female/18	5 days	-	None/survived
Clozapine	Wu MK. (2015)⁶²Taiwan	Male/54	1 month	-	None/survived
Daunorubicin	Shakya P (2021)²¹Nepal	Male/2	2 weeks	-	None/died by day 6.
Diclofenac	Shetty SR (2010)⁵⁹India	Female/45	6 days	-	Betamethasone, prednisolone/survived
Efavirenz	Paik S (2015)b²⁰India	Female/23	2 weeks	Naranjo Scale-ProbableWHO-UMC System-Probable/Likely	Corticosteroids (name not given)/survived
Enzalutamide	Deng M (2021)¹⁸China	Male/92	10 days	Naranjo Scale-Probable	Hydrocortisone/survived
Flurbiprofen	Khan AA. (2022)⁴²Pakistan	Female/30	14 days	-	Dexamethasone/survived
Hydroxychloroquine	Al-Barzinji N (2023)²⁶Iraq	Female/30	2 days	-	Dexamethasone/survived
	Davoodi L (2020)³⁶Iran	Female/42	2 days	-	None/survived
Ibuprofen	Gui MZ (2021)³⁹China	Female/9	Less than 5 days	Naranjo Scale-Probable	Methylprednisolone, gamma globulin/survived
Ivermectin	Aroke D (2017)¹⁷Cameroon	Male/38	1 day	-	Dexamethasone, prednisone/survived
Lamotrigine	Yasui-Furukori N. (2014)⁶⁴Japan	Female/19	13 days	-	Methylprednisolone/survived
Methotrexate	Akıncı B (2017)²⁵Turkey	Male/8	Unclear	-	Methylprednisolone/survived
Ofloxacin	Shaw B (2023)⁵⁸USA	Female/36	>24 h	-	Methylprednisolone/survived
Oxcarbazepine	Beken B. (2017)³⁰Turkey	Male/6	5 days	-	None/survived
	Lin LC. (2009)⁴⁶Taiwan	Male/9	14 days	-	Steroid (names not specified)/survived
	Sharma SR (2011)⁵⁷India	Male/21	14 days	-	Steroid (names not specified)/survived
Paclitaxel	Hiraki A (2004)⁴⁰Japan	Male/53	3 days	-	Methylprednisolone/survived
Phenytoin	Kandil AO. (2010)⁴¹USA	Male/46	8 days	-	Dexamethasone/survived
Ribociclib	López-Gómez V (2019)⁴⁷Spain	Female/77	4 months	-	Etanercept, cyclosporine/survived
Valproic acid	Castana O. (2009)³²Greece	Male/38	1 day	-	Gamma globulin/survived

Abbreviations: USA-United States of America; ALDEN-algorithm of drug causality for epidermal necrolysis; WHO-UMC-World Health Organization-Uppsala Monitoring Centre.

Reported time of onset of SJS related symptoms from the first dose ranged from 12 h to 4 months, with 19 (38.8%) case reports indicating onset of symptoms of less than 7 days.^{17,19,26–28,30,32–36,39,40,50,51,58–60,63}

Regarding use of a causality assessment instrument, eight (16.3%) case reports used Naranjo Scale with a rating of probable for seven reports^{16,18–20,22,39,50} and one possible²⁹; 2 (4.1%) case reports used the WHO-UMC System, and both reports were rated probable/likely.^20,22 Three reports (6.1%) used the ALDEN instrument with two rated as very probably^43,52 and one probable.¹⁹ Seven (14%) case reports discussed possible concurrent disease as a factor in the risk of drug-induced SJS, which included positive COVID-19 status of the patients,^36,58 pulmonary impairment,⁵¹ the presence of the human immune-deficiency virus,¹⁷ presence of giant cell arteritis,²⁴ nuclear receptor transcription factor 4a suppression,⁴⁸ and risk related to the Human Leukocyte Antigen.²³ Six case reports (12.2%) implicating carbamazepine, enzalutamide, daunorubicin, tocilizumab, acetaminophen and efavirenz discussed other coadministered drugs as possible factors in the drug-induced SJS. For carbamazepine, the case report explicitly stated no other drug was implicated.⁴³ For enzalutamide coadministered with goserelin¹⁸ and daunorubicin coadministered with methotrexate²¹; the second drugs were excluded based on temporal association between onset of SJS and time of drug challenge; while for tocilizumab coadministered with prednisone,²⁴ the second drug was excluded based on the disappearance of symptoms with tocilizumab dechallenge. For acetaminophen, the coadministered clarithromycin was excluded based on negative results using a lymphocyte stimulation test protocol⁵¹ and for efavirenz, the coadministered tenofovir was excluded based on the absence of published literature associating tenofovir with SJS.²⁰

Systemic immunosuppressant therapy with steroids was reported for 37 (75.5%) case reports. Of these case reports, 30 (61.2%) indicated patients received only steroids to manage SJS; 5 patients received steroid plus globulin,^{24,31,39,45,61} one patient received steroid plus globulin and cyclosporine⁵¹ and one patient received steroid plus azathioprine and cyclosporine.⁵⁶ One patient received globulin only³² and one patient received etanercept and cyclosporine.⁴⁷ There were 10 patients who were not given any systemic immunosuppressant drug.^{19,21,23,30,34–36,43,49,62} Of the 49 included case reports, 2 (4.1%) patients died; in one case, the patient did not receive systemic immunosuppressant and died of sepsis 6 days post-diagnosis²¹; the second case received systemic immunosuppressant (methylprednisolone, immunoglobulin and cyclosporine)and died from pulmonary impairment, 90 days post-diagnosis.⁵¹

Discussion

In this study, forty-nine case reports matched the inclusion criteria and critical analysis using a modification of the ISoP/ISPE guidelines for adverse events related to drugs, rated the quality of the case reports from moderate to strong. All case reports were compliant with providing name of the implicated drug, patient’s age and sex, as well as the description of the adverse event. However, for most of the case reports, there was no use of a causality assessment instrument; neither was there discussion of the possible involvement of concurrent diseases and coadministered drugs in the adverse event.

An interesting finding of our study was that most of the case reports originated from countries of the Asian continent. This representation is possibly related to what is known of higher prevalence of cutaneous severe adverse drug reactions in these populations and may support the need for interventions to reduce patients’ risk, such as implementation of genetic screening.^66,67

The most common drugs identified were carbamazepine, pembrolizumab, azithromycin, and oxcarbazepine; these results are consistent with previous case report publications and case reports of the FAERS database.^7,8 A higher frequency pembrolizumab induced SJS in comparison to other monoclonal antibodies was observed. Although this may be a reflection of drug entry into the market and its increasing dominance,^9,68 previous publications have also identified this emerging trend and have suggested safety concerns.^69,70 Therefore, consideration should be given to the further examination of the relationship between SJS and this humanized monoclonal antibody.

Systemic use of steroids was the preferred immunosuppressant administered for most patients; although such treatment intervention remains inadequately supported by clinical evidence, including meta-analytic studies using the Cochrane Skin Specialised Registry.^5,71,72 Interestingly, there is evidence of superiority of etanercept to systemic steroid therapy in promoting skin healing and reducing mortality⁵; this drugs was only administered in one study.⁴⁷

Case reports are considered low level on the hierarchy of evidence-based medicine and therefore have limited external validity. They however provide evidence from real-world clinical practice and although most of the included drug induced SJS case reports did not utilize causality assessment, there was much information to advance discussions on minimizing patient risk. Our results are also limited by a level of publication bias, as financial constraints excluded access to articles unavailable free and publications requiring translation to English.

In conclusion, most of the case reports were of moderate to strong quality; weaknesses were related to the absence of information about patient comorbidities and coadministered drugs. The published case reports of SJS were predominately from countries known to be at higher risk of this adverse event and the common drugs identified are consistent with current trends. The emerging greater number of case reports implicating pembrolizumab may be an important safety concern. With the anticipated increase in demand for this drug, studies are required to further examine the relationship with SJS. Finally, therapy with systemic steroids was the preferred immunosuppressant, although clinical benefit of such therapy remains unsupported. With the absence of standardize treatment protocols, enriching case reports with details of outcomes of patients may provide useful clinical evidence.

Supplemental Material

Supplemental Material - Rapid review of drug induced Stevens Johnson Syndrome case reports from 2003 to 2023: Trends among monoclonal antibodies and systemic immunosuppressant therapy

Supplemental Material for Rapid review of drug induced Stevens Johnson Syndrome case reports from 2003 to 2023: Trends among monoclonal antibodies and systemic immunosuppressant therapy by Maxine Gossell-Williams, Gabrielle McLaren, Rojay Clarke, Shenae Douglas, Devonne Gayle and Kerrian Guthrie in International Journal of Risk & Safety in Medicine.

Footnotes

ORCID iD

Maxine Gossell-Williams

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

References

Ardern-Jones

Friedmann

. Skin manifestations of drug allergy. Br J Clin Pharmacol 2011; 71(5): 672–683.

Sekula

Dunant

Mockenhaupt

, et al. Comprehensive survival analysis of a cohort of patients with Stevens–Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol 2013; 133(5): 1197–1204.

Haanen

Carbonnel

Robert

, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28: iv119–iv142.

Thompson

Schneider

Brahmer

, et al. Management of immunotherapy-related toxicities, version 1.2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2019; 17(3): 255–289.

Jacobsen

Olabi

Langley

, et al. Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome. Cochrane Database Syst Rev 2022; 3(3): CD013130.

Thong

BY-H

. Drug-induced Stevens Johnson syndrome and toxic epidermal necrolysis: interpreting the systematic reviews on immunomodulatory therapies. Asia Pac Allergy 2023; 13(2): 72–76.

Wang

Varghese

Bassir

, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review of PubMed/MEDLINE case reports from 1980 to 2020. Front Med 2022; 9: 949520.

Fei

Shen

Cai

. Causes of drug-induced severe cutaneous adverse reaction epidermal necrolysis (EN): an analysis using FDA adverse event reporting System (FAERS) database. Clin Cosmet Investig Dermatol 2023; 16: 2249–2257.

Kardile

Kulkarni

Nadar

, et al. Monoclonal antibodies in oncology: a decade of novel options. Cell Biochem Biophys 2023; 81(3): 395–408.

10.

Garritty

Gartlehner

Nussbaumer-Streit

, et al. Cochrane Rapid Reviews Methods Group offers evidence-informed guidance to conduct rapid reviews. J Clin Epidemiol 2021; 130: 13–22.

11.

Kelly

Arellano

Barnes

, et al. Guidelines for submitting adverse event reports for publication. Pharmacoepidemiol Drug Saf 2007; 16(5): 581–587.

12.

Agbabiaka

Savović

Harris

, et al. The development of a tool to assess the quality of case reports of adverse events. Int J Risk Saf Med 2008; 20(3): 123–133.

13.

Fernando

. The management of toxic epidermal necrolysis. Australas J Dermatol 2012; 53(3): 165–171.

14.

Armijo-Olivo

Stiles

Hagen

, et al. Assessment of study quality for systematic reviews: a comparison of the Cochrane collaboration risk of bias tool and the effective public health practice project quality assessment tool: methodological research. J Eval Clin Pract 2012; 18(1): 12–18.

15.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Bmj 2021; 372: n71.

16.

Anis

Meher

. Allopurinol-induced stevens–johnson syndrome (SJS). Clin Pharmacol 2023; 15: 99–105.

17.

Aroke

Tchouakam

Awungia

, et al. Ivermectin induced Steven–Johnsons syndrome: case report. BMC Res Notes 2017; 10: 1–4.

18.

Deng

Chai

Yang

, et al. Stevens-Johnson syndrome caused by enzalutamide: a case report and literature review. Front Oncol 2021; 11: 736975.

19.

Jawaro

Kumar

Pistun

, et al. Stevens-Johnson syndrome associated with chlordiazepoxide. J Pharm Technol 2018; 34(2): 82–85.

20.

Paik

Pal

Sen

, et al. A suspected case of Efavirenz-induced Stevens–Johnson syndrome. Drug Saf Case Rep 2015; 2: 1–5.

21.

Shakya

Sharma Nepal

. Daunorubicin induced Stevens-Johnson syndrome: a case report. Clin Case Rep 2021; 9(7): e04475.

22.

Srinivasan

Karthikeyan

Sivaneswari

, et al. Clinical condition and medication therapy of amoxicillin-induced Stevens-Johnson syndrome: a case report. Aging Med 2019; 2(4): 227–229.

23.

Tran

Nguyen

Vercueil

. Successful treatment of a paroxysmal kinesigenic dyskinesia patient with carbamazepine-induced Stevens-Johnson syndrome using oxcarbazepine monotherapy: a case report. Case Rep Neurol 2022; 13(3): 598–604.

24.

Venkateswaran

Khianey

Generoso

. Stevens johnson syndrome in a patient with giant cell arteritis during short term tocilizumab therapy. Cureus 2020; 12(4): e7662.

25.

Akıncı

Siviş

Şahin

, et al. Stevens-Johnson Syndrome associated with methotrexate treatment for acute lymphoblastic leukemia: a case report. Arch Argent Pediatr 2018; 116(3): e459–e462.

26.

Al-Barzinji

Jalal

. Hydroxychloroquine-induced stevens–johnson syndrome in the patient with systemic lupus erythematosus: a case report in Kurdish region-Iraq. Mediterr J Rheumatol 2023; 34(4): 547–549.

27.

Alsulami

Aldahasi

Aljabri

, et al. Drug-induced stevens-johnson syndrome without skin manifestations: a case report and review of literature. Cureus 2023; 15(3): e36318.

28.

Bae

Park

Kim

, et al. Stevens-johnson syndrome induced by carbamazepine treatment in a patient who previously had carbamazepine induced pruritus-a case report. Korean J Pain 2013; 26(1): 80–83.

29.

Batool

Voloshyna

Usama

, et al. The Co-existence of agranulocytosis and stevens-johnson syndrome (SJS) in carbamazepine therapy: a case report. Cureus 2022; 14(9): e28917.

30.

Beken

Can

Örencik

, et al. Oxcarbazepine-induced Stevens–Johnson syndrome: a pediatric case report. Oxf Med Case Reports 2017; 2017(6): omx028.

31.

Cao

Zhi

, et al. Pembrolizumab-induced autoimmune Stevens-Johnson syndrome/toxic epidermal necrolysis with myositis and myocarditis in a patient with esophagogastric junction carcinoma: a case report. Transl Cancer Res 2021; 10(8): 3870–3876.

32.

Castana

Rempelos

Anagiotos

, et al. Stevens-Johnson syndrome: a case report. Ann Burns Fire Disasters 2009; 22(3): 147–151.

33.

Chirasuthat

Chayavichitsilp

. Atezolizumab-induced Stevens-Johnson syndrome in a patient with non-small cell lung carcinoma. Case Rep Dermatol 2018; 10(2): 198–202.

34.

Cravens

Sherman

Sawaya

. Ciprofloxacin-induced Stevens-Johnson syndrome with grapefruit juice consumption: a case report. Cureus 2019; 11(1): e3827.

35.

Das

Medhi

Chakravarty

, et al. Mucous membrane grafting for the post-Steven–Johnson syndrome symblepharon: a case report. Indian J Ophthalmol 2011; 59(3): 231–233.

36.

Davoodi

Jafarpour

Kazeminejad

, et al. Hydroxychloroquine-induced Stevens–Johnson syndrome in COVID-19: a rare case report. Oxf Med Case Reports 2020; 2020(6): omaa042.

37.

Diep

Aluri

Crane

, et al. Stevens-Johnson syndrome in a patient of color: a case report and an assessment of diversity in medical education resources. Cureus 2022; 14(2): e22245.

38.

Gracia-Cazaña

Padgett

Calderero

, et al. Nivolumab-associated Stevens-Johnson syndrome in a patient with lung cancer. Dermatol Online J 2021; 27(3): 13030/qt2897t6dq.

39.

Gui

M-Z

Yin

X-D

, et al. Ibuprofen induced Stevens-Johnson syndrome and liver injury in children: a case report. Transl Pediatr 2021; 10(6): 1737–1742.

40.

Hiraki

Aoe

Murakami

, et al. Stevens-Johnson syndrome induced by paclitaxel in a patient with squamous cell carcinoma of the lung: a case report. Anticancer Res 2004; 24(2C): 1135–1138.

41.

Kandil

Dvorak

Mignano

, et al. Multifocal Stevens-Johnson syndrome after concurrent phenytoin and cranial and thoracic radiation treatment, a case report. Radiat Oncol 2010; 5: 1–5.

42.

Khan

Rashid

Khan

, et al. Diagnosis and treatment of flurbiprofen-induced Stevens–Johnson syndrome: a rare case report. Clin Case Rep 2022; 10(9): e6365.

43.

Khor

Lim

Tan

, et al. Cross-reactivity in AED-induced severe cutaneous adverse reaction: a case report. J Investig Allergol Clin Immunol 2016; 26(5): 329–331.

44.

Kurian

Desai

Rafferty

, et al. Case report: alpelisib-induced stevens–johnson syndrome. Front Oncol 2022; 12: 954027.

45.

Chen

, et al. Case Report: sintilimab-induced Stevens-Johnson Syndrome in a patient with advanced lung adenocarcinoma. Front Oncol 2023; 13: 912168.

46.

Lin

L-C

Lai

P-C

Yang

S-F

, et al. Oxcarbazepine-induced Stevens-Johnson syndrome: a case report. Kaohsiung J Med Sci 2009; 25(2): 82–86.

47.

López-Gómez

Yarza

Muñoz-González

, et al. Ribociclib-related stevens-johnson syndrome: oncologic awareness, case report, and literature review. J Breast Cancer 2019; 22(4): 661–666.

48.

Machida

Yamazaki

Kouda

, et al. A case report involving suppressed nuclear receptor transcription factors 4a1 and Stevens-Johnson syndrome induced by a single dose of pembrolizumab and successfully treated with early steroid administration, resulting in complete remission of stage III lung cancer. J Pharm Health Care Sci 2022; 8(1): 29.

49.

Mishra

Singh

Gaur

, et al. Lip synechiae: a rare complication of azithromycin-associated Stevens–Johnson syndrome. Natl J Maxillofac Surg 2019; 10(2): 232–234.

50.

Mkhoyan

Hashmi

Khan

, et al. Stevens-Johnson syndrome: a case report of possible cephalosporin-induced cutaneous adverse reaction. J Infect Dev Ctries 2023; 17(10): 1493–1496.

51.

Nakamura

Ochi

Chisaka

, et al. Acetaminophen‐induced Stevens–Johnson syndrome with lethal lung injury: a case report. Clin Case Rep 2022; 10(9): e6294.

52.

Paik

Sen

Das

, et al. Allopurinol induced stevens - johnson syndrome - a case report. J Clin Diagn Res 2015; 9(2): Wj01–Wj02.

53.

Rajput

Sagari

Durgavanshi

, et al. Paracetamol induced Steven-Johnson syndrome: a rare case report. Contemp Clin Dent 2015; 6(Suppl 1): S278–S281.

54.

Salama

Lawrance

. Stevens-Johnson syndrome complicating adalimumab therapy in Crohn's disease. World J Gastroenterol 2009; 15(35): 4449–4452.

55.

Sandhu

Binod

Bhandari

, et al. Pembrolizumab-associated Stevens-Johnson syndrome in a patient with metastatic non-small cell lung cancer: a case report. Cureus 2023; 15(7):e41439.

56.

Shabrawishi

Qanash

. Bronchiolitis obliterans after cefuroxime-induced Stevens-Johnson syndrome. Am J Case Rep 2019; 20: 171–174.

57.

Sharma

Yeolekar

. Oxcarbazepine-induced Stevens Johnson syndrome: a rare case report. Indian Dermatol Online J 2011; 2(1): 13–15.

58.

Shaw

Madden

Crespo

, et al. A rare case of severe stevens-johnson syndrome triggered by topical Ofloxacin. Am J Case Rep 2023; 24: e941992.

59.

Shetty

Chatra

Shenai

, et al. Stevens-Johnson syndrome: a case report. J Oral Sci 2010; 52(2): 343–346.

60.

Shrestha

Yadav

, et al. Cefixime induced Steven Johnson syndrome: a case report from Bangladesh. Ann Med Surg 2022; 79: 104089.

61.

J-Y

Kang

, et al. Pembrolizumab-induced Stevens-Johnson syndrome in advanced squamous cell carcinoma of the lung: a case report and review of literature. World J Clin Cases 2022; 10(18): 6110–6118.

62.

M-K

Chung

C-K

, et al. The severe complication of Stevens–Johnson syndrome induced by long-term clozapine treatment in a male schizophrenia patient: a case report. Neuropsychiatr Dis Treat 2015; 11: 1039–1041.

63.

Zhu

, et al. Nursing care of a boy seriously infected with Steven–Johnson syndrome after treatment with azithromycin: a case report and literature review. Medicine 2018; 97(1): e9112.

64.

Yasui-Furukori

Hashimoto

Tsuruga

, et al. Comorbidity of Stevens–Johnson syndrome and neutropenia associated with lamotrigine: a case report. Gen Hosp Psychiatry 2014; 36(6): e9–e11.

65.

Rahim Ai

Ibrahim

Salim Fn

, et al. Health information engagement factors in Malaysia: a content analysis of facebook use by the ministry of health in 2016 and 2017. Int J Environ Res Publ Health 2019; 16(4): 591.

66.

Arrieta-Bolaños

Hernández-Zaragoza

Barquera

. An HLA map of the world: a comparison of HLA frequencies in 200 worldwide populations reveals diverse patterns for class I and class II. Front Genet 2023; 14: 866407.

67.

Chan

Jin

Loh

, et al. Progress in understanding the genomic basis for adverse drug reactions: a comprehensive review and focus on the role of ethnicity. Pharmacogenomics 2015; 16(10): 1161–1178.

68.

Tsuchikama

Anami

SYY

, et al. Exploring the next generation of antibody-drug conjugates. Nat Rev Clin Oncol 2024; 21(3): 203–223.

69.

Bolton

Chen

Hawthorne

, et al. Systematic review: monoclonal antibody-induced subacute cutaneous lupus erythematosus. Drugs R&D 2020; 20: 319–330.

70.

Ellis

Vierra

Millsop

, et al. Dermatologic toxicities to immune checkpoint inhibitor therapy: a review of histopathologic features. J Am Acad Dermatol 2020; 83(4): 1130–1143.

71.

Grünwald

Mockenhaupt

Panzer

, et al. Erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis - diagnosis and treatment. J Dtsch Dermatol Ges 2020; 18(6): 547–553.

72.

Chang

H-C

Wang

T-J

Lin

M-H

, et al. A review of the systemic treatment of Stevens–Johnson syndrome and toxic epidermal necrolysis. Biomedicines 2022; 10(9): 2105.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.56 MB