Research

JAMA Dermatology | Original Investigation

Assessment of Treatment Approaches and Outcomes

in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Insights From a Pan-European Multicenter Study
Khalaf Kridin, MD, PhD; Marie-Charlotte Brüggen, MD, PhD; Ser-Ling Chua, PhD; Anette Bygum, DMSci;
Sarah Walsh, MB, BCh; Mirjam C. Nägeli, MD; Vesta Kucinskiene, MD, PhD; Lars French, MD, PhD;
Florence Tétart, MD; Biagio Didona, MD; Brigitte Milpied, MD; Annamari Ranki, MD, PhD;
Carmen Salavastru, MD, PhD; Eva Březinová, MD, PhD; Sapna Divani-Patel, MBBS, BSc; Tine Lorentzen, MD;
Julie Loft Nagel, MD; Skaidra Valiukeviciene, MD; Viktorija Karpavičiūtė, MD, PhD; George-Sorin Tiplica, MD;
Eva Oppel, MD; Anna Oschmann, MD; Nicolas de Prost, MD, PhD;
Artem Vorobyev, MD; Saskia Ingen-Housz-Oro, MD

Supplemental content
IMPORTANCE Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are
severe drug reactions associated with a high rate of mortality and morbidity. There is no
consensus on the treatment strategy.

OBJECTIVE To explore treatment approaches across Europe and outcomes associated with
the SJS/TEN disease course, as well as risk factors and culprit drugs.

DESIGN, SETTING, AND PARTICIPANTS A retrospective pan-European multicenter cohort study

including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted.
A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31,
2019, and data were collected from a follow-up period of 6 weeks.

MAIN OUTCOMES AND MEASURES Risk factors for severe acute-phase complications
(acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks
following admission were evaluated using a multivariable-adjusted logistic regression model.
One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis
(SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity.

RESULTS Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the
mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit
drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal
anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the
most common suspected agents. Treatment approaches ranged from best supportive care
only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%),
cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%)
developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal
body surface area detachment (ⱖ30%) was found to be independently associated with
severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12;
P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality
(fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with
a higher frequency of greater than or equal to 20% increase in body surface area detachment
in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk
of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and
intravenous immunoglobulins were associated with a decreased risk of infections (adjusted
OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was
found between treatment groups.

CONCLUSIONS AND RELEVANCE This cohort study noted differences in treatment strategies
for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies Author Affiliations: Author
to be conducted and registries to be developed. affiliations are listed at the end of this
article.
Corresponding Author: Saskia
Ingen-Housz-Oro, MD, Dermatology
Department, AP-HP, Henri Mondor
Hospital, 51 avenue du Maréchal de
JAMA Dermatol. 2021;157(10):1182-1190. doi:10.1001/jamadermatol.2021.3154 Lattre de Tassigny, 94000 Créteil,
Published online August 25, 2021. France (saskia.oro@aphp.fr).

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 Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
S
tevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN), or Lyell syndrome, are rare, delayed-
type hypersensitivity reactions associated with high lev-
els of morbidity and mortality.1,2 The clinical hallmark of SJS
and TEN is epidermal and mucosal detachment and necrosis.
The 2 entities are defined by the body surface area (BSA) of de-
tachable or detached skin: less than 10% of the BSA affected
in SJS, 10% to 30% in overlap syndrome, and more than
30% in TEN.1,3,4 Disease prognosis is determined by various
clinical and biological factors. Some of these parameters, such
as patient age and more than 10% BSA involvement, have been
integrated in risk prediction models, such as the Score of
Toxic Epidermal Necrolysis (SCORTEN)5 and, more recently,
the ABCD-10.6 SCORTEN, which was used in our analysis, in-
cludes 7 clinical and biological parameters collected at base-
line and is a predictive score for acute-phase mortality. The
severity levels range from 0 to 7, with 7 the highest level.
In SJS/TEN treatment, the first and most important mea-
sure is the immediate discontinuation of the culprit drug.7
In addition, best supportive care has been recognized as a cor-
nerstone of SJS/TEN treatment.8-10 In contrast, no consensus
exists on the best adjuvant treatment. The rarity and severity
of SJS/TEN have been obstacles to performing controlled clini-
cal trials. Current clinical practices, including the use of sys-
temic agents, such as cyclosporine, systemic glucocorticoids,
intravenous immunoglobulins (IVIGs), and antitumor necro-
sis factor (TNF) agents, are based only on retrospective case
reports of series and empirical experience. The association of
these agents with the outcome, however, has not been proven
in prospective trials.11,12
In March 2017, the European Union created the European
Reference Network for rare skin diseases (ERN-skin) to offer
European Union citizens with rare skin diseases the benefits
of specialized care anywhere in Europe. ERN-skin includes
56 health care settings (ie, reference centers) located in 18
European countries. ToxiTEN is the subgroup of ERN-skin dedi-
cated to SJS/TEN. In this multicenter, retrospective cohort
study, we aimed to explore and compare the clinical profile,
culprit drugs, prognostic factors, and treatment approaches
for SJS/TEN across members of the ToxiTEN group.
Methods
Study Design
The present study was designed as a pan-European multi-
center, longitudinal retrospective cohort study, performed by
the ToxiTEN group (eFigure in the Supplement). Patients were
recruited from 13 health care settings across 10 European coun-
tries: Czech Republic, Denmark, Finland, France, Germany,
Italy, Lithuania, Romania, Switzerland, and the UK (eTable 1
in the Supplement). All participating institutes were refer-
ence centers with expertise in the management of SJS/TEN.
All adult (age ≥18 years) patients diagnosed with SJS/TEN
between January 1, 2015, and December 31, 2019, in these
centers were included in the study. This study followed the
Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) reporting guideline for cohort studies.
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Original Investigation Research
Key Points
Question What are the treatment approaches for
Stevens-Johnson syndrome and toxic epidermal necrolysis across
Europe and their association with the disease course in the acute
phase, as well as prognostic factors and culprit drugs?
Findings In this cohort study, among 212 patients, treatment
approaches ranged from best supportive care only to systemic
glucocorticoids, intravenous immunoglobulins, cyclosporine, and
antitumor necrosis factor agents; the 6-week mortality rate was
20.8% and antibiotics were the most frequent culprit drugs.
Meaning The findings of this study suggest differences in
treatment strategies for Stevens-Johnson syndrome and toxic
epidermal necrolysis in Europe and highlight the importance of
prospective therapeutic studies and registries.
The study was conducted according to the ethical guidelines
at the respective institutions and ethical approval was obtained
by all participating centers in accordance with the Declaration
of Helsinki.13 The participants provided informed consent
and the data were deidentified.
Study Population and Covariates
The diagnosis of SJS/TEN was established by expert consul-
tants specialized in inpatient dermatology on the basis of com-
patible clinical and histologic features.1,2 Before enrollment in
the study, all cases of SJS/TEN were validated by the princi-
pal investigator at each site through comprehensive medical
records review, based on predefined clinical and histologic
criteria (eg, presence of epidermal detachment, involvement
of >2 mucosae, atypical target lesions, histologic evidence of
epidermal necrosis, and exclusion of differential diagnoses).
Medical records were manually reviewed for each partici-
pant. The following variables, which were routinely collected dur-
ing the patients’ hospital stays, were systematically retrieved and
entered in a standardized form: demographic characteristics,
SCORTEN at admission,5 initial and maximal BSA extent of epi-
dermal detachment/detachable skin, affected mucosal surfaces,
comorbidities, culprit drugs or other putative predisposing fac-
tors, hospitalization features, and the therapeutic regimens used.
Eligible patients were followed up at regular intervals for
6 weeks after the initial presentation to estimate survival sta-
tus. In addition, study participants were longitudinally evalu-
ated for the occurrence of severe acute complications. The
latter variables were defined as the development of at least
1 of the following conditions during the disease course: (1) sep-
ticemia, (2) pulmonary infection, (3) acute kidney injury, and
(4) respiratory distress necessitating mechanical ventilation.
Subsequently, data on this longitudinal follow-up were retro-
spectively collected by all participating centers.
Statistical Analysis
Baseline characteristics were described as means (SDs) for con-
tinuous variables and percentages for categorical values. The
comparison between different variables was performed using
the χ2 test for categorical variables and t test for continuous
variables. The fully adjusted model included all variables that
were found significant in the univariate analysis.
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 Research Original Investigation Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

ine), patients receiving supportive therapy served as a refer-

Table 1. Demographic and Clinical Characteristics
of 212 Patients With SJS/TEN ence group. Only patients treated with a single agent were
included, and outcome measures were adjusted for age and
Characteristic No. (%)
SCORTEN. Findings were considered significant at unpaired
Demographic characteristics
and 2-sided P < .05. Statistical analyses were performed using
Age at diagnosis (n = 204), y
SPSS, version 25 (IBM Corp).
Mean (SD) 51.0 (19.3)
Median (range) 49.2 (18.1-94.7)
Sex (n = 211)
Men 77 (36.3) Results
Women 134 (63.7)
Demographic Characteristics
Race and ethnicity The study population comprised 212 patients; with data on sex
White 142 (67.0) available on 211 individuals, 77 (36.3%) were men and 134
Asian 25 (11.8) (63.7%) were women. The mean (SD) age at diagnosis of
African 38 (17.9) SJS/TEN was 51.0 (19.3) years, and the median age was 49.2
Unknowna 7 (3.3) years (range, 18.1-94.7 years). Most patients were of White race
Countries (142 [67.0%]), whereas 38 (17.9%) were of African ancestry and
Czech Republic 2 (0.9) 25 (11.8%) were of Asian ancestry. Table 1 further delineates
Denmark 13 (6.1) the demographic features of study participants.
Finland 5 (2.4) The mean (SD) SCORTEN was estimated at 2.2 (1.5);
France 95 (44.8) the mean (SD) percentage of BSA epidermal detachment/
Germany 10 (4.7) detachable skin at presentation was 27.0% (23.8%) and, at the
Italy 7 (3.3) maximal activity of the disease, was 39.5% (29.2%). The oral
Lithuania 12 (5.7) mucosa was the most frequently affected mucosal surface (184
Romania 5 (2.4) of 207 [88.9%]), followed by the ocular (138 of 207 [66.7%]),
Switzerland 16 (7.5) genital (129 of 207 [62.3%]), laryngeal/pharyngeal (75 of 207
UK 47 (22.2) [36.2%]), and anal (44 of 203 [21.7%]) mucosae. The mean (SD)
Clinical manifestations
number of involved mucosal surfaces was 2.8 (1.3), and 66
(31.1%) patients had 4 or more affected mucosae.
SCORTEN (n = 193)
Mean (SD) 2.2 (1.5)
Median (range) 2.0 (0.0-7.0)
Culprit Drugs and Other Putative Triggers
A culprit drug was identified in 176 (83.0%) patients. Nonsul-
BSA detachment, mean (SD)
fonamide antibiotics (21.2%), anticonvulsants (18.9%), non-
At presentation (n = 186) 27.0 (23.8)
steroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%),
Maximal (n = 191) 39.5 (29.2)
and sulfonamides (including sulfonamide antibiotics, 10.4%)
Distribution of mucosal lesions
were the most common triggering agents (Figure, A). Regard-
Oral (n = 207) 184 (88.9)
ing antibiotics, β-lactams (44.4%), fluoroquinolones (35.6%),
Ocular (n = 207) 138 (66.7)
and vancomycin (11.1%) were the most common classes (Figure,
Laryngeal/pharyngeal (n = 207) 75 (36.2)
B). Among patients with anticonvulsant-induced SJS/TEN,
Genital (n = 207) 129 (62.3) exposure to aromatic anticonvulsants (eg, carbamazepine,
Anal (n = 203) 44 (21.7) phenytoin, and phenobarbital), was documented in 87.5% of
Abbreviations: BSA, body surface area; SCORTEN, Score of Toxic Epidermal the patients (Figure, C).
Necrolysis; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. In 36 patients (17.0%), a detailed medical history did not
a
No further breakdown of categories comprising unknown race is available. reveal exposure to potential culprit medications. In these
There were 7 patients with unknown ethnic background.
patients, the development of SJS/TEN was attributed to
Mycoplasma pneumoniae infection (4 [11.1%]), other infec-
The independent associations between demographic, dis- tious agents (6 [16.7%]), and autoimmune comorbidities
ease-specific, and comorbidity variables with the risk of mor- (5 [13.9%]). No trigger was found in the remaining 21 (58.3%)
tality and severe complications were evaluated using multi- patients who had no culprit drug identified.
variable-adjusted logistic regression and are reported as odds
ratios (ORs) and 95% CIs. Entry and removal limits were set at Management and Treatment Regimens
P < .05 in the univariate analysis. The covariates included in Our analysis showed that treatment for most patients was man-
the regression model were treated as dichotomous and en- aged in dermatology inpatient wards (144 [69.6%]), whereas
compassed, among others, age, with a cutoff set at 40 years treatment for 100 patients (48.3%) was managed in intensive
in accordance with age limit in SCORTEN, and a SCORTEN of care units and, for 40 patients (19.3%), in burn units; 72 pa-
2 (the median value of this severity score in our cohort). In the tients (34.0%) received treatment in both dermatology and
analysis evaluating outcome measures in the frequent treat- intensive care units during the acute phase. One hundred thirty-
ment regimens (systemic glucocorticoids, IVIG, and cyclospor- two patients (62.3%) were referred from other health care fa-

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 Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Original Investigation Research

cilities, and 80 individuals (37.7%) were directly admitted to the

Figure. Distribution of General Culprit Drugs, Culprit Antibiotics,
participating centers (eTable 2 in the Supplement). The mean Culprit Anticonvulsants, and Treatment Modalities
(SD) duration of inpatient hospital stays was 25.0 (28.3) days.
Treatment for 81 (38.2%) patients was managed with sup- A Overall
portive treatment only. Systemic glucocorticoids were the most
Antibiotics
frequently used therapy, being administered to 75 patients
Anticonvulsants
(35.4%). Other agents used included IVIG (50 [23.6%]), cyclo-
NSAIDs
sporine (22 [10.4%]), and antitumor necrosis factor (7 [3.3%])
Allopurinol
(Figure, D; eTable 3 in the Supplement).
Sulfonamides

Burden of and Risk Factors for Mortality and Complications Fluconazole

Forty-four patients (20.8%) died during the initial 6 weeks of Other

the study. Table 2 reports univariate and multivariable analy- No suspected drug
ses to identify risk factors for mortality within the first 6 weeks.
0 5 10 15 20 25
SCORTEN greater than or equal to 2 was significantly associ- Incidence, %
ated with susceptibility to mortality (fully adjusted OR, 10.30;
95% CI, 3.82-27.78; P < .001). Other demographic variables, B Antibiotics
comorbid conditions, disease-specific features, and treat-
Lactams
ment modalities were not independently associated with the
Fluoroquinolones
risk of mortality (Table 2).
Vancomycin
We assessed the frequency and risk factors of severe acute-
Other
phase complications. A total of 135 patients (63.7%) experi-
enced severe complications; septicemia occurred in 59 pa- 0 10 20 30 40 50
tients (27.8%) and pulmonary infections occurred in 58 patients Incidence, %
(27.3%). Acute kidney injury developed in 43 patients (20.3%),
and 67 patients (31.6%) required mechanical ventilation C Anticonvulsants

(eTable 2 in the Supplement). Aromatic

Table 3 presents the risk factors for severe acute-phase Nonaromatic
complications during the course of SJS/TEN. Maximal BSA Aromatic and nonaromatic
detachment greater than or equal to 30% was found to be in-
0 20 40 60 80 100
dependently associated with the occurrence of severe acute-
Incidence, %
phase complications (fully adjusted OR, 2.49; 95% CI, 1.21-
5.12; P = .01). Although ocular involvement (age- and severity-
D SJS treatment
adjusted OR, 2.25; 95% CI, 1.17-4.32; P = .02) and cyclosporine
treatment (age- and severity-adjusted OR, 4.17; 95% CI, 1.17- Systemic corticosteroids

14.89; P = .03) were associated with complications after ad- Intravenous immunoglobulin

justing for age and severity, they fell short of significance in Cyclosporine

the fully adjusted model. TNF antagonists

G-CSF
Disease Outcomes With Different Treatment Supportive only
Table 4 delineates SJS/TEN-related outcomes and complica-
0 10 20 30 40 50
tions among patients who received monotherapy with sys-
Incidence, %
temic glucocorticoids (n = 52), IVIG (n = 28), or cyclosporine
(n = 20) compared with those treated supportively (n = 81). G-CSF indicates granulocyte-colony stimulating factor; NSAIDs, nonsteroidal
Following the adjustment for age and SCORTEN, systemic anti-inflammatory drugs; SJS, Stevens-Johnson syndrome; TNF, tumor
necrosis factor.
glucocorticoids were associated with a lower risk of exten-
sive disease (defined as maximal BSA detachment ≥30%; ad-
justed OR, 0.16; 95% CI, 0.05-0.51; P = .002), and cyclospor- CI, 0.05-0.63; P = .008). The baseline characteristics of pa-
ine was associated with a greater than or equal to 20% increase tients in the different treatment groups are outlined in eTable 4
in BSA detachment during the disease course (adjusted OR, in the Supplement.
3.44; 95% CI, 1.12-10.52; P = .03).
Cyclosporine use was associated with an increased risk for
any type of infection (adjusted OR, 7.16; 95% CI, 1.52-33.74;
P = .01). Systemic glucocorticoids were associated with a
Discussion
reduced risk of any infection (adjusted OR, 0.40; 95% CI, 0.18- The aim of this multicenter retrospective study was to ex-
0.88; P = .02) and mechanical ventilation (adjusted OR, 0.34; plore the profile of patients, culprit drugs, treatment ap-
95% CI, 0.12-0.96; P = .05). Treatment with IVIG was associ- proaches, and prognostic factors of SJS/TEN across expert
ated with a decreased risk of septicemia (adjusted OR, 0.17; 95% centers within European countries. In line with previous data,1

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 Research Original Investigation Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Table 2. Risk Factors for Mortality Within 6 Weeks of Follow-up in Patients With SJS/TEN as Identified by Logistic Regression Modela

No./No. (%) patients

Died in the Did not die Age- and
first 6 wk in the first 6 wk Unadjusted P severity-adjusted P Fully adjusted P
Variable (n = 44) (n = 157) OR (95% CI) value OR (95% CI)b value OR (95% CI)c value
Men 20/44 (45.5) 52/157 (33.1) 1.68 (0.85-3.32) .13 NA NA NA NA
Age at diagnosis ≥40 y 37/43 (86.0) 95/156 (60.9) 3.96 (1.58-9.94) .002d 1.89 (0.67-5.34) .23 2.03 .25
(0.61-6.78)
African ancestry (vs White and 8/44 (18.2) 29/157 (18.5) 0.98 (0.41-2.33) .97 NA NA NA NA
Asian ancestry)
Comorbid conditions
Autoimmune disease 11/44 (25.0) 24/157 (15.3) 1.85 (0.83-4.15) .13 NA NA NA NA
Iatrogenic 17/44 (38.6) 19/157 (12.1) 4.57 (2.11-9.91) <.001d 2.35 (0.94-5.85) .07 1.95 .20
immunosuppression (0.70-5.42)
Cancer 16/44 (36.4) 20/157 (12.7) 3.91 (1.81-8.48) <.001d 1.48 (0.59-3.67) .40 1.00 >.99
(0.35-2.87)
HIV 4/44 (9.1) 7/157 (4.5) 2.14 (0.60-7.68) .23 NA NA NA NA
Culprit drug
Anticonvulsants 4/44 (9.1) 36/150 (24.0) 0.32 (0.11-0.95) .03d 0.45 (0.14-1.52) .20 0.55 .38
(0.14-2.12)
Antibiotics 14/44 (31.8) 27/150 (18.0) 2.13 (1.00-4.54) .048d 1.30 (0.53-3.21) .56 1.15 .79
(0.41-3.29)
Allopurinol 9/44 (20.5) 15/150 (10.0) 2.31 (0.94-5.73) .06 NA NA NA NA
Sulfonamide 4/44 (9.1) 18/150 (12.0) 0.73 (0.24-2.92) .59 NA NA NA NA
Fluconazole 2/44 (4.5) 2/150 (1.3) 3.52 .19 NA NA NA NA
(0.48-25.18)
NSAIDs 4/44 (9.1) 19/150 (12.0) 0.73 (0.24-2.29) .59 NA NA NA NA
No suspected drug 3/44 (6.8) 23/150 (15.3) 0.40 (0.12-1.42) .15 NA NA NA NA
Other putative triggers
Mycoplasma 0/35 (0.0) 8/138 (5.8) 0.94 (0.90-0.98) .15 NA NA NA NA
Other infections 1/44 (2.3) 5/157 (3.2) 0.71 (0.08-6.21) .75 NA NA NA NA
Disease severity
SCORTEN>2 35/43 (81.4) 35/146 (24.0) 13.88 <.001d 12.04 <.001d 10.30 <.001d
(5.89-32.69) (5.01-28.94) (3.82-27.78)
BSA at presentation >10% 36/41 (87.8) 86/141 (61.0) 4.61 .001d NA NA NA NA
(1.70-12.45)
Maximal BSA≥30% 28/40 (70.0) 70/143 (49.0) 2.43 (1.15-5.16) .02d NA NA NA NA
Affected mucosal surfaces
Oral 40/44 (90.9) 143/157 (91.1) 0.98 (0.31-3.14) .97 NA NA NA NA
Ocular 27/44 (61.4) 110/157 (70.1) 0.68 (0.34-1.36) .27 NA NA NA NA
Larynx/pharynx 19/44 (43.2) 55/157 (35.0) 1.41 (0.71-2.78) .32 NA NA NA NA
Genital 23/44 (52.3) 108/157 (68.8) 0.50 (0.25-0.98) .04d 0.72 (0.32-1.62) .43 0.77 .57
(0.31-1.89)
Anal 7/42 (16.7) 40/154 (26.0) 0.57 (0.24-1.39) .21 NA NA NA NA
Treatment modalities
Supportive care only 13/44 (29.5) 64/157 (40.8) 0.61 (0.30-1.25) .18 NA NA NA NA
Systemic glucocorticoids 16/44 (36.4) 52/157 (31.1) 1.15 (0.57-2.32) .69 NA NA NA NA
Cyclosporine 3/44 (6.8) 19/157 (12.1) 0.53 (0.15-1.89) .32 NA NA NA NA
IVIG 16/44 (36.4) 34/157 (21.7) 2.07 (1.00-4.26) .046d 2.31 (0.78-6.79) .13 1.61 .36
(0.58-4.52)
Anti-TNF agents 3/44 (6.8) 4/157 (2.5) 2.80 .17 NA NA NA NA
(0.60-13.00)
b
Abbreviations: BSA, body surface area; IVIG, intravenous immunoglobulin; Severity was defined based on SCORTEN.
NA, not applicable; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds c
Entry and removal limits to fully adjusted multivariable analysis were set at
ratio; SCORTEN, Score of Toxic Epidermal Necrolysis; SJS, Stevens-Johnson P < .05. Given the collinearity between SCORTEN and BSA involvement,
syndrome; TEN, toxic epidermal necrolysis; TNF, tumor necrosis factor. only the former was included in the multivariable model.
a
This analysis was confined to 201 patients in whom follow-up data 6 weeks d
Significant at P < .05.
following the diagnosis was available.

among the 212 adults with SJS/TEN included in our cohort, no amides), including β-lactams, were the most common identi-
culprit drug could be identified in approximately 20% of the fied culprit drugs in these patients, followed by allopurinol and
patients with SJS/TEN. Antibiotics (not including sulfon- anticonvulsants. Although these are the overall most com-

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 Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Original Investigation Research

Table 3. Risk Factors for Severe Acute Complications in Patients With SJS/TEN as Identified by Logistic Regression Model

No./No. (%) patients Age- and

With acute Without acute severity-
complications complications Unadjusted OR P adjusted OR P Fully adjusted P
Variable (n = 135) (n = 77) (95% CI) value (95% CI)a value OR (95% CI)b value
Men 49/135 (36.4) 28/77 (36.4) 0.98 (0.56-1.78) .99 NA NA NA NA
Age at diagnosis ≥40 y 91/131 (69.5) 45/73 (61.6) 1.42 (0.78-2.58) .26 NA NA NA NA
African ancestry (vs White and 28/135 (20.7) 10/77 (13.0) 1.75 (0.80-3.84) .16 NA NA NA NA
Asian ancestry)
Comorbid conditions
Autoimmune disease 23/135 (17.0) 14/77 (18.2) 0.92 (0.44-1.92) .83 NA NA NA NA
Iatrogenic 27/135 (20.0) 10/77 (13.0) 1.68 (0.77-3.68) .20 NA NA NA NA
immunosuppression
Cancer 27/135 (20.0) 10/77 (13.0) 1.68 (0.76-3.68) .20 NA NA NA NA
HIV 10/135 (7.4) 2/77 (2.6) 3.00 (0.64-14.06) .15 NA NA NA NA
Culprit drug
Anticonvulsants 23/134 (17.2) 17/70 (24.3) 0.65 (0.32-1.31) .22 NA NA NA NA
Antibiotics 25/134 (18.7) 20/70 (27.4) 0.57 (0.29-1.13) .11 NA NA NA NA
Allopurinol 20/134 (14.9) 4/70 (5.7) 2.90 (0.95-8.83) .05 NA NA NA NA
Sulfonamide 16/134 (11.9) 6/70 (8.6) 1.45 (0.54-3.88) .46 NA NA NA NA
Fluconazole 2/134 (1.5) 2/70 (2.9) 0.52 (0.07-3.74) .51 NA NA NA NA
NSAIDs 16/134 (11.9) 9/70 (12.9) 0.92 (0.38-2.20) .85 NA NA NA NA
No suspected drug 19/134 (14.2) 7/70 (10.0) 1.20 (0.51-2.78) .40 NA NA NA NA
Other putative triggers
Mycoplasma 5/115 (4.3) 3/68 (4.4) 0.99 (0.23-4.26) .98 NA NA NA NA
Other infections 5/135 (3.7) 1/77 (1.3) 2.92 (0.34-25.49) .31 NA NA NA NA
Severity NA NA NA NA
SCORTEN>2 54/129 (41.9) 18/64 (28.1) 1.84 (0.96-3.52) .06 NA NA NA NA
BSA at presentation >10% 93/122 (76.2) 31/64 (48.4) 3.41 (1.79-6.50) <.001c NA NA NA NA
Maximal BSA≥30% 81/126 (64.3) 18/65 (27.7) 4.70 (2.44-9.04) <.001c 4.43 <.001c 2.49 .01
(2.31-8.50) (1.21-5.12)
Affected mucosal surfaces
Oral 123/135 (91.1) 66/77 (85.7) 1.71 (0.72-4.08) .22 NA NA NA NA
Ocular 97/135 (71.9) 43/77 (55.8) 2.02 (1.12-3.63) .02c 2.25 .02c 1.77 .12
(1.17-4.32) (0.86-3.63)
Larynx/pharynx 55/135 (40.7) 20/77 (26.0) 1.96 (1.06-3.62) .03c 1.76 .09 1.49 .29
(0.91-3.41) (0.71-3.12)
Genital 91/135 (67.4) 43/77 (55.8) 1.64 (0.92-2.91) .09 NA NA NA NA
Anal 27/131 (20.6) 20/76 (26.3) 0.73 (0.37-1.41) .35 NA NA NA NA
Treatment modalities
Supportive care only 50/135 (37.0) 31/77 (40.3) 0.87 (0.49-1.55) .64 NA NA NA NA
Systemic glucocorticoids 42/135 (31.1) 33/77 (42.9) 0.60 (0.34-1.08) .09 NA NA NA NA
Cyclosporine 19/135 (14.1) 3/77 (3.9) 4.04 (1.16-14.13) .02c 4.17 .03c 3.42 .08
(1.17-14.89) (0.86-13.53)
IVIG 35/135 (25.9) 15/77 (19.5) 1.45 (0.73-2.86) .29 NA NA NA NA
Anti-TNF agents 3/135 (2.2) 4/77 (5.2) 0.42 (0.09-1.90) .24 NA NA NA NA
b
Abbreviations: BSA, body surface area; IVIG, intravenous immunoglobulin; Entry and removal limits to fully adjusted multivariable analysis were set at
NA, not applicable; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds P < .05.
ratio; SCORTEN, Score of Toxic Epidermal Necrolysis; SJS, Stevens-Johnson c
Significant at P < .05.
syndrome; TEN, toxic epidermal necrolysis; TNF, tumor necrosis factor.
a
Severity was defined based on SCORTEN.

mon causative agents of SJS/TEN, our results differ from
other studies. A study of a cohort of 187 patients from South
Korea identified allopurinol as the most common culprit
drug, followed by carbamazepine and lamotrigine.14 In a
multicenter retrospective study from the US, sulfamethoxa-
zole with trimethoprim was identified as the most common
culprit drug.15 In the EuroSCAR study, antibiotics (except
cotrimoxazole) were considered as lower risk drugs.16 The
divergences between these observations can, at least par-
tially, be associated with the genetic background, ie, differ-
ences in risk human leukocyte antigen allele expression,
which varies among races/ethnicities1: most of our patients
were of White race. Moreover, regional differences in pre-
scription practices, such as the use of cotrimoxazole for uri-

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 Research Original Investigation Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Table 4. Difference in Disease Outcomes and Complications Among Patients With SJS/TEN Receiving Systemic Glucocorticoids, IVIG, Cyclosporine,
and Supportive Therapya
Systemic corticosteroids
monotherapy IVIG monotherapy Cyclosporine monotherapy Supportive care
(n = 52) (n = 28) (n = 20) (n = 81),
Adjusted OR P Adjusted OR P Adjusted OR P adjusted OR
Characteristic (95% CI)b value (95% CI)b value (95% CI)b value (95% CI)b
SJS/TEN-related outcomes
Maximal BSA detachment ≥30% 0.16 (0.05-0.51) .002c 2.19 (0.73-6.58) .16 2.77 (0.89-8.60) .08 1 [Reference]
Increase in BSA detachment 0.66 (0.19-2.31) .52 2.07 (0.72-5.97) .18 3.44 (1.12-10.52) .03c 1 [Reference]
≥20% during the disease course
Complications
Any infection 0.40 (0.18-0.88) .02c 0.60 (0.24-1.52) .28 7.16 (1.52-33.74) .01c 1 [Reference]
c
Septicemia 0.43 (0.17-1.09) .07 0.17 (0.05-0.63) .008 2.74 (0.95-7.92) .06 1 [Reference]
Acute kidney injury 0.61 (0.20-1.82) .37 1.68 (0.56-5.00) .35 2.24 (0.64-7.91) .21 1 [Reference]
Mechanical ventilation 0.34 (0.12-0.96) .04c 1.25 (0.45-3.45) .67 2.04 (0.69-6.10) .20 1 [Reference]
Mortality within the first 6 wk 0.79 (0.24-2.62) .70 1.48 (0.42-5.21) .55 1.00 (0.17-5.70) >.99 1 [Reference]
b
Abbreviations: BSA, body surface area; IVIG, intravenous immunoglobulin; Adjusted for age and Score of Toxic Epidermal Necrolysis.
SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. c
Significant at P < .05.
a
Patients receiving systemic therapy in addition to systemic corticosteroids
(n = 23), IVIG (n = 22), and cyclosporine (n = 2) were excluded.

nary tract infections or soft tissue infections, could further
contribute to this observation.17
There is an overall consensus on the importance of
best supportive care, which is recognized in various national
guidelines as the cornerstone of SJS/TEN treatment to reduce
mortality.9,10,18-20 In contrast, the efficacy of adjuvant thera-
pies for SJS/TEN is still debated. To our knowledge, there are
neither guidelines nor comparative studies on the use of ad-
juvant agents in SJS/TEN, and their use mostly relies on case
series, case reports, and clinical experience. Our study, thus,
provides a comparative report on the wide range of these ad-
juvant therapies and our results mirror the center-dependent
diversity of therapeutic approaches in SJS/TEN, ranging from
IVIG,21,22 systemic glucocorticoids,23 antitumor necrosis fac-
tor agents,24-26 and cyclosporine27-29 to supportive care only.
Although our study was not designed or able to compare the
efficacy of different treatment approaches, it yielded some
interesting results: cyclosporine was associated with an in-
crease of BSA affected and an overall higher risk of infec-
tions, and IVIG was associated with a decreased risk of sep-
sis. Systemic glucocorticoids were associated with a lower rate
of patients with a maximal affected BSA greater than or equal
to 30% over the disease course. Although our results are not
sufficient for conclusions to be made as to the superiority of
any adjuvant treatment, they suggest the need to investigate
the associations of different treatments not only with mortal-
ity, but also with the occurrence of life-threatening complica-
tions and epidermal healing during the acute phase. Given that
our study only covered the acute-phase observation period,
further studies are warranted to explore whether patients may
exhibit different clinical outcomes, including long-term com-
plications and mortality.
The mortality rate of 20.8% at 6 weeks in our study was simi-
lar to some studies,30,31 but higher than in other studies.15,19 Our
investigation suggests that the extent of BSA detachment and
respiratory failure were risk factors for both mortality and life-
threatening complications during the acute phase.5,32-34
Limitations
This study has limitations. First, we did not include children
because triggers, prognosis, and management of SJS/TEN in
children differ considerably from those in adults. Further-
more, childhood SJS/TEN may be misdiagnosed as erythema
multiforme.35 Second, although our multicenter study in-
cluded various countries and centers, with substantially dif-
fering numbers of patients included per center, the selection
of the sites may have biased our findings. Third, owing to the
retrospective data collection, caution is warranted when draw-
ing conclusions regarding treatment strategies. Prospective
clinical trials are needed to evaluate the efficacy of the differ-
ent adjuvant treatments in SJS/TEN.
Conclusions
This multicenter European retrospective study on 212 adults
with SJS/TEN provides an overview on patients’ profiles, drug
triggers, prognosis, and treatment regimens within the
ERN-skin network. This study describes the current diversity
of treatment approaches across centers and countries. Fu-
ture studies and registries, such as IRTEN (the international
registry of TEN),2 may aim to prospectively collect compre-
hensive clinical and biological information on more patients
with SJS/TEN to ultimately improve the treatment.

ARTICLE INFORMATION Published Online: August 25, 2021. Author Affiliations: Lübeck Institute of
Accepted for Publication: July 5, 2021. doi:10.1001/jamadermatol.2021.3154 Experimental Dermatology, University of Lübeck,
Lübeck, Germany (Kridin, Vorobyev); Azrieli Faculty
of Medicine, Bar-Ilan University, Safed, Israel

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 Treatment Approaches and Outcomes in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
(Kridin); Department of Dermatology, University
Hospital of Zurich, Zurich, Switzerland (Brüggen,
Nägeli); Faculty of Medicine, University of Zurich,
Zurich, Switzerland (Brüggen, Nägeli); Medical
Campus Davos, Davos, Switzerland (Brüggen);
ToxiTEN group, European Reference Network for
Rare Skin Diseases, Paris, France (Brüggen, Chua,
Bygum, Walsh, Kucinskiene, French, Tétart, Didona,
Milpied, Ranki, Salavastru, Březinová, Tiplica,
Vorobyev, Ingen-Housz-Oro); Department of
Dermatology, University Hospitals Birmingham NHS
Foundation Trust, Birmingham, United Kingdom
(Chua, Divani-Patel); Department of Dermatology
and Allergy Center, Odense University Hospital,
Clinical Institute, University of Southern Denmark,
Odense, Denmark (Bygum, Lorentzen, Nagel);
Department of Dermatology, King’s College
Hospital, London, United Kingdom (Walsh);
Department of Skin and Venereal Diseases,
Lithuanian University of Health Sciences (LUHS),
Hospital of LUHS Kauno Klinikos, European
Reference Network for Rare and Complex Diseases
of the Skin members, Kaunas, Lithuania
(Kucinskiene, Valiukeviciene); Department of Skin
and Venereal Diseases, Lithuanian University of
Health Sciences, Kaunas, Lithuania (Kucinskiene,
Valiukeviciene, Karpavičiūtė); Department of
Dermatology, University Hospital, Munich
University of Ludwig Maximilian, Munich, Germany
(French, Oppel, Oschmann); Dr Phillip Frost
Department of Dermatology and Cutaneous
Surgery, University of Miami Miller School of
Medicine, Miami, Florida (French); Toxic Bullous
Dermatoses and Severe Drug Reactions reference
center, TOXIBUL FIMARAD network, Assistance
Publique-Hôpitaux de Paris, Henri Mondor
Hospital, Créteil, France (Tétart, Milpied, de Prost,
Ingen-Housz-Oro); Department of Dermatology,
Inserm U519, Rouen University Hospital, Rouen,
France (Tétart); Rare Disease Unit, I Dermatology
Division, Istituto Dermopatico dell’Immacolata,
IRCCS, Rome, Italy (Didona); Department of
Dermatology, Saint André Hospital, Bordeaux,
France (Milpied); Department of Dermatology,
Allergology and Venereology, University of Helsinki,
Helsinki, Finland (Ranki); Helsinki University
Hospital, Inflammation Center, Helsinki, Finland
(Ranki); Carol Davila University of Medicine and
Pharmacy, Bucharest, Romania (Salavastru, Tiplica);
Department of Pediatric Dermatology, Colentina
Clinical Hospital, Bucharest, Romania (Salavastru);
First Department of Dermatovenereology, Masaryk
University Faculty of Medicine, St Ann’s Faculty
Hospital in Brno, Brno, Czech Republic (Březinová);
Department of Dermatology, Colentina Clinical
Hospital, Carol Davila University of Medicine and
Pharmacy, Bucharest, Romania (Tiplica); Intensive
care unit, AP-HP, Henri Mondor Hospital, Créteil,
France (de Prost); Department of Dermatology,
University Medical Center Schleswig-Holstein,
Lübeck, Germany (Vorobyev); Dermatology
Department, AP-HP, Henri Mondor Hospital,
Créteil, France (Ingen-Housz-Oro); University
Paris-Est Créteil EpiDermE, Créteil, France
(Ingen-Housz-Oro).
Author Contributions: Drs Kridin and
Ingen-Housz-Oro had full access to all of the
data in the study and take responsibility for the
integrity of the data and the accuracy of the data
analysis. Drs Kridin and Brüggen contributed
equally, and Drs Vorobyev and Ingen-Housz-Oro
contributed equally.
jamadermatology.com
© 2021 American Medical Association. All rights reserved.
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Concept and design: Kridin, Brüggen, Walsh, Nägeli,
Tétart, Didona, Březinová, Tiplica, de Prost,
Vorobyev, Ingen-Housz-Oro.
Acquisition, analysis, or interpretation of data:
Kridin, Chua, Bygum, Walsh, Nägeli, Kucinskiene,
French, Milpied, Ranki, Salavastru, Březinová,
Divani-Patel, Lorentzen, Loft Nagel, Valiukeviciene,
Karpavičiūtė, Tiplica, Oppel, Oschmann, Vorobyev,
Ingen-Housz-Oro.
Drafting of the manuscript: Kridin, Brüggen, Ranki,
Salavastru, Divani-Patel, Karpavičiūtė, Tiplica,
Vorobyev, Ingen-Housz-Oro.
Critical revision of the manuscript for important
intellectual content: Kridin, Brüggen, Chua, Bygum,
Walsh, Nägeli, Kucinskiene, French, Tétart, Didona,
Milpied, Ranki, Salavastru, Březinová, Lorentzen,
Loft Nagel, Valiukeviciene, Oppel, Oschmann,
de Prost, Vorobyev.
Statistical analysis: Kridin, Divani-Patel,
Karpavičiūtė, Vorobyev.
Obtained funding: Kridin.
Administrative, technical, or material support:
Kridin, Brüggen, Bygum, Walsh, Nägeli,
Kucinskiene, Ranki, Divani-Patel, Oppel, Oschmann,
Vorobyev.
Supervision: Kridin, Brüggen, Bygum, Walsh, Nägeli,
French, Didona, Březinová, Valiukeviciene, de Prost.
Conflict of Interest Disclosures: Dr Walsh
reported receiving nonfinancial support from
UCB Pharma for sponsored attendance at meeting
outside the submitted work. Dr Salavastru reported
receiving nonfinancial support and personal fees
from Leo Pharma, and nonfinancial support from
AbbVie outside the submitted work; in addition,
Dr Salavastru had a patent for Springer Nature
Switzerland AG with royalties paid. Dr Tiplica
reported receiving personal fees from Antibiotice,
nonfinancial support from A&D Pharma Marketing
& Sales Services, nonfinancial support from EGIS
Pharmaceutical PLC, and nonfinancial support from
Sanofi Romania SRL outside the submitted work.
No other disclosures were reported.
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