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From the Cochrane Library: Systemic Interventions for Steven-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS/TEN Overlap Syndrome

From the Cochrane Library: Systemic Interventions for Steven-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS/TEN Overlap Syndrome

From the Cochrane Library: Systemic Interventions for Steven-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS/TEN Overlap Syndrome

Research Letter

1Department of Dermatology, Rutgers Robert Wood Johnson Medical School, Somerset, NJ, United States

2Department of Dermatology, Rutgers New Jersey Medical School, Newark, NJ, United States

3Department of Dermatology, New York Institute of Technology, Glenhead, NY, United States

4Department of Dermatology, Rao Dermatology, Atlantic Highlands, NJ, United States

5Department of Dermatology, Hennepin Healthcare, Minneapolis, MN, United States

6Department of Dermatology, University of Minnesota, Minneapolis, MN, United States

7Department of Dermatology, Veterans Affairs Medical Center, Minneapolis, MN, United States

Corresponding Author:

Gaurav Nitin Pathak, PharmD

Department of Dermatology

Rutgers Robert Wood Johnson Medical School

1 World’s Fair Drive

Somerset, NJ, 08873

United States

Phone: 1 732235 9895


Steven-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are a spectrum of potentially life-threatening, rare, and severe cutaneous adverse reactions that are triggered by medication use typically within weeks of medication initiation. The pathogenesis of SJS/TEN is theorized to be a T lymphocyte–mediated immune response to an antigen of the offending medication causing epidermal necrosis [1]. There is limited evidence to support the use of therapies, such as glucocorticoids, intravenous immunoglobulins (IVIGs), cyclosporine, and etanercept, for the treatment of SJS and TEN [1]. We aim to summarize the key findings of a Cochrane review on the effects of systemic therapies for SJS/TEN.

To evaluate systemic therapies for SJS/TEN, a systematic review of randomized controlled trials (RCTs) and prospective observational comparative studies (up to March 2021) of patients of all ages with SJS/TEN was conducted [1]. The primary end points were disease-specific mortality (DSM) and adverse events leading to the discontinuation of systemic treatment therapy. Secondary end points included time to complete re-epithelialization, intensive care unit length of stay, total hospital length of stay, illness sequelae, and adverse events.

In total, 9 studies with a total of 308 patients from across 7 countries were included in the analysis, of which 3 were RCTs and 6 were prospective observational studies; 2 studies were included in a meta-analysis. The risk of bias for the three RCTs was respectively rated as high, moderate, and low; all the prospective comparative studies were rated as having a high risk of bias. The interventions that were assessed included systemic corticosteroids, tumor necrosis factor-α inhibitors, and others (Table 1).

The overall level of certainty for the parameters of interest was low, so most findings were “uncertain.” It was uncertain if corticosteroids had a higher risk of DSM versus no corticosteroids (relative risk [RR] 2.55, 95% CI 0.72-9.03). It was also uncertain if there was a difference between IVIGs and no IVIGs in terms of DSM (RR 0.33, 95% CI 0.04-2.91), time to re-epithelialization (mean difference −2.93, 95% CI −4.4 to −1.46 d), or length of hospital stay (mean difference −2.00, 95% CI −5.81 to 1.81 d). Etanercept did not significantly reduce DSM compared to corticosteroids (RR 0.51, 95% CI 0.16-1.63; P=.72), and serious adverse events, such as sepsis and respiratory failure, occurred in treatment with both groups. It was also uncertain if there was any difference between the cyclosporine and IVIG groups in terms of the risk of DSM (RR 0.13, 95% CI 0.02-0.98). A summary of other comparator studies is included in Table 2.

Table 1. Key characteristics of included trials.
Study (author, year)Study designSample size, nInterventionOutcome measured
Azfar et al [2], 2010Prospective observational study40Corticosteroids (dose unknown) vs supportive careDisease-specific mortality
González-Herrada et al [3], 2017Prospective controlled study22Cyclosporine (POa 3 mg/kg/d or IVb 1 mg/kg/d until re-epithelialization, then taper off 10 mg/d every 48 h) vs IVIGc (0.75 g/kg/d for 4 d; lower dose for renal insufficiency), systemic corticosteroids (37.5- to 100-mg prednisone equivalents for 4 d), or supportive careAll-cause mortality, expected death rate based on SCORTENd, time to stabilization of BSAe involvement, time to re-epithelialization start, and time to complete re-epithelialization
Han et al [4], 2017Prospective comparator study28Plasmapheresis (1-time dose of 1000 mL of Ringer-Locke and 2-3 L of plasma at 1 L/h) vs IVIG or corticosteroids (unknown dose)Hospital length of stay
Jagadeesan et al [5], 2013Prospective comparator study36IVIG (0.2- to 0.5-g/kg cumulative dose over 3 d) and IV dexamethasone (0.1-0.3 mg/kg/d; tapered within 1-2 wk) vs IV dexamethasone (0.1-0.3 mg/kg/d; rapidly tapered within 1-3 wk)Disease-specific mortality, AEsf leading to discontinuation, other AEs, mean days to full skin healing, mean length of hospital stay, and illness sequelae
Kakourou et al [6], 1997Prospective comparative study16Corticosteroids (methylprednisolone bolus 4 mg/kg/d for 2 d after fever subsided) vs supportive care onlyMortality
Paquet et al [7], 2014Open-label randomized controlled trial10IV NACg in 5% glucose over 20-h period (150 mg/kg in 250 mL over first h; then 150 mg/kg in 500 mL for 4 h; and, lastly, 150 mg/kg in 1000 mL over 15 h) and IV infliximab (5 mg/kg over 2 h) vs NAC-only regimen (same as former)Disease-specific mortality
Saraogi et al [8], 2016Prospective observational study43IV corticosteroids, IVIG, and combination of corticosteroids and IVIG vs supportive careArrest of disease progression, time to re-epithelialization, and mortality
Wang et al [9], 2018Open-label randomized controlled clinical trial91Subcutaneous etanercept 25 mg (50 mg if >65 kg) twice weekly until skin lesions healed (n=48) vs IV prednisolone 1-1.5 mg/kg/d until skin lesions healed (n=43)Disease-specific mortality and other AEs

Wolkenstein et al [10], 1998Double-blind randomized controlled trial22Thalidomide 200 mg BIDh PO × 5 d vs placebo at same dosing regimenDisease-specific mortality

aPO: per os.

bIV: intravenous.

cIVIG: intravenous immunoglobulin.

dSCORTEN: Score for Toxic Epidermal Necrolysis.

eBSA: body surface area.

fAE: adverse event.

gNAC: N‐acetylcysteine.

hBID: twice per day.

Table 2. Summary of key study findings.
ComparisonNumber of patients (number of studies)Anticipated absolute effects (95% CI)Relative effect (95% CI)Certainty of evidence (GRADEa)
Corticosteroids vs supportive care56 (2 OSb) [2,6]DSMc: 91 per 1000 (supportive care) vs 232 per 1000 (corticosteroid); TTCRd: NRe; ICU-LOSf: NR; TH-LOSg: NR; AE/DCh: NRDSM: 2.55 (0.72 to 9.03); TTCR: NR; ICU-LOS: NR; TH-LOS: NR; AE/DC: NRVery low
IVIGi and supportive care vs supportive care36 (1 OS) [5]DSM: 55 (6 to 386) per 1000 (IVIG) vs 167 per 1000 (supportive care); TTCR: mean 10.93 d, mean difference 2.93 d lower (4.4 d lower to 1.46 d lower); ICU-LOS: NR; TH-LOS: mean 15.33 d, mean difference 2.00 d lower (5.81 d lower to 1.81 d higher); AE/DC: NRDSM: 0.33 (0.04 to 2.91); TTCR: NR; ICU-LOS: NR; TH-LOS: NR; AE/DC: NRVery low
Etanercept vs supportive careNo studies fit criteriaN/AjN/AN/A
Cyclosporine vs supportive careNo studies fit criteriaN/AN/AN/A
IVIG vs corticosteroidsNo studies fit criteriaN/AN/AN/A
Etanercept vs corticosteroids91 (1 RCTk) [9]DSM: 163 per 1000 (corticosteroids) vs 83 (26 to 265) per 1000 (etanercept); TTCR: NR; ICU-LOS: NR; TH-LOS: NR; AE/DC: NRDSM: 0.51 (0.16 to 1.63); TTCR: NR; ICU-LOS: NR; TH-LOS: NR; AE/DC: NRLow
Cyclosporine vs corticosteroidsNo studies fit criteriaN/AN/AN/A
Etanercept vs IVIGNo studies fit criteriaN/AN/AN/A
Cyclosporine vs other treatments (IVIG: n=4; corticosteroids: n=1; no specified treatment: n=1)22 (1 OS) [3]DSM: 500 per 1000 (other treatments) vs 65 (10 to 468) per 1000 (cyclosporine); TTCR: NR; ICU-LOS: NR; TH-LOS: NR; AE/DC: NRDSM: 0.13 (0.02 to 0.98); TTCR: NR; ICU-LOS: NR; TH-LOS: NR; AE/DC: NRVery low
Etanercept vs cyclosporineNo studies fit criteriaN/AN/AN/A
N-acetylcysteine and infliximab vs infliximab alone10 (1 OS) [7]NRDSM: 2.00 (0.26 to 15.62)NR
Thalidomide vs placebo22 (1 RCT) [10]NRDSM: 2.78 (1.04 to 7.40)NR
Plasmapheresis vs other treatments28 (1 OS) [4]NRTH-LOS: mean difference −7.37 (−16.09 to 1.35) dNR

aGRADE: Grading of Recommendations, Assessment, Development, and Evaluation.

bOS: observational study.

cDSM: disease-specific mortality of Steven-Johnson syndrome and toxic epidermal necrolysis.

dTTCR: time to complete re-epithelialization.

eNR: not reported.

fICU-LOS: intensive care unit length of stay.

gTH-LOS: total hospital length of stay.

hAE/DC: adverse effects leading to discontinuation of Steven-Johnson syndrome/toxic epidermal necrolysis therapy.

iIVIG: intravenous immunoglobulin.

jN/A: not applicable.

kRCT: randomized controlled trial.

The authors of the original review concluded that “etanercept (25 mg [50 mg if weight > 65 kg]) twice weekly ‘until skin lesions healed’) may reduce DSM compared to corticosteroids (intravenous prednisolone 1 to 1.5 mg/kg/day ‘until skin lesions healed’) (RR 0.51, 95% CI 0.16 to 1.63; 1 study; 91 participants; low‐certainty evidence); however, the CIs were consistent with possible benefit and possible harm” [1]. Overall, data from the included studies were limited, with few direct clinical comparator studies for the different therapeutic agents assessed. Future multicenter large-scale studies are needed to better outline SJS/TEN medication therapy and evaluate agents of choice in disease management.

Conflicts of Interest

BR is a speaker for Incyte and Amgen. AAJ has received the Cochrane Scholarship for the original Cochrane review from the American Academy of Dermatology. All other authors have no conflicts of interest to declare.

Editorial Notice

This article is based on a Cochrane Review previously published in the Cochrane Database of Systematic Reviews 2022, Issue 3, DOI: 10.1002/14651858.CD013130.pub2 (see for information). Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and Cochrane Database of Systematic Reviews should be consulted for the most recent version of the review.

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DSM: disease-specific mortality
IVIG: intravenous immunoglobulin
RCT: randomized controlled trial
RR: relative risk
SJS: Steven-Johnson syndrome
TEN: toxic epidermal necrolysis

Edited by R Dellavalle; submitted 16.02.23; peer-reviewed by E Brenaut, D Zheng; comments to author 12.07.23; revised version received 20.09.23; accepted 27.12.23; published 30.01.24.


©Gaurav Nitin Pathak, Thu Minh Truong, Amit Singal, Viktoria Taranto, Babar K Rao, Audrey A Jacobsen. Originally published in JMIR Dermatology (, 30.01.2024.

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