SCARs in China

pISSN 1013-9087ㆍeISSN 2005-3894

Ann Dermatol Vol. 31, No. 5, 2019 https://doi.org/10.5021/ad.2019.31.5.545

ORIGINAL ARTICLE

Severe Cutaneous Adverse Reactions: A Single-Center

Retrospective Study of 173 Patients in China
Zhongyi Xu*, Jie Shen1,*, Yiwen Yang, Ruoyue Yuan, Leihong Flora Xiang, Chengfeng Zhang

Department of Dermatology, Huashan Hospital, Fudan University, 1Department of Cancer Prevention, Fudan University Shanghai Cancer
Center, Shanghai, China

Background: Severe cutaneous adverse reactions (SCAR) to onset to corticosteroids treatment were correlated with
drugs are a crucial public health issue and the use of systemic SCAR prognosis. Conclusion: Prompt short-course systemic
corticosteroids in SCAR has been controversial. Objective: corticosteroids use is associated with early-stage skin lesions
To analyze clinical features, causative drugs, treatment, out- remission without influencing the disease mortality.
comes, and prognostic factors of SCAR in the case-series of Lymphadenopathy and eosinophilia were the independent
173 patients, and add more information to the debate of us- poor prognostic factors of SCAR. (Ann Dermatol 31(5) 545∼
ing systemic corticosteroids in SCAR management. Methods: 554, 2019)
A retrospective study of 173 SCAR patients diagnosed with
drug reaction with eosinophilia and systemic symptoms -Keywords-
(DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal Acute generalized exanthematous pustulosis, Drug re-
necrolysis (TEN) or acute generalized exanthematous pustu- action with eosinophilia and systemic symptoms, Stevens-
losis (AGEP) at a tertiary care institution in China between Johnson syndrome, Systemic corticosteroids treatment,
January 2014 and December 2017 was conducted. Results: Toxic epidermal necrolysis
Of 173 patients, allopurinol, carbamazepine, and antibiotics
are the most frequently implicated drugs for DRESS (40.4%),
SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, INTRODUCTION
there is a strongly negative correlation between early cortico-
steroids use and the progression (p=0.000) and severity Severe cutaneous adverse reactions (SCAR) to drugs are
(p=0.01) of skin lesions. However, there is no association among the most life-threatening conditions involving the
between early corticosteroids use and the mortality of SCAR skin, mainly encompassing drug reaction with eosino-
(odds ratio: 1.01, 95% confidence interval: 0.95∼1.08). In philia and systemic symptoms (DRESS) syndrome, Stevens-
addition, lymphadenopathy, eosinophilia, and interval from Johnson syndrome (SJS) and toxic epidermal necrolysis
(TEN), and acute generalized exanthematous pustulosis
Received May 30, 2019, Revised July 9, 2019, Accepted for publication July (AGEP)1. DRESS is a hypersensitivity reaction, characte-
15, 2019
rized by a variable combination of heterogenous clinical
Corresponding author: Chengfeng Zhang, Department of Dermatology, 2
presentations , such as fever, lymphadenopathy, eosino-
Huashan Hospital, Fudan University, 12 Middle Wulumuqi Road, Shanghai
200040, China. Tel: 86-02152889999, Fax: 86-02152887783, E-mail: philia, facial edema, erythroderma and even internal or-
[email protected] gan involvement3. SJS/TEN is known as a drug-induced
ORCID: https://orcid.org/0000-0002-1302-5667
hypersensitivity reaction, showing atypical target lesions
*These two authors contributed equally to this work.
and bullous lesions with acute exanthema. SJS and TEN
This is an Open Access article distributed under the terms of the Creative
are differentiated by the extent of epidermal detachment
Commons Attribution Non-Commercial License (http://creativecommons.
org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, (SJS with body surface area [BSA] ＜10%, TEN with BSA
distribution, and reproduction in any medium, provided the original work ＞30%, and anything in-between called SJS–TEN overlap
is properly cited.
syndrome)4. AGEP is characterized by the rapid develop-
Copyright © The Korean Dermatological Association and The Korean
Society for Investigative Dermatology
ment of multiple non-follicular, sterile pustules on an ery-

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Z Xu, et al

thematous base, mainly attributed to drugs, especially an- Table 1. Causative drugs of SCAR
5
tibiotics, in the majority of cases . Associated drug Case (%)
Given the severity of SCAR, numerous studies have been
DRESS
conducted. However, to date no specific treatment has
Allopurinol 23 (40.4)
been universally accepted. Meanwhile, information of Sulfasalazine 8 (14.0)
SCAR patients in Asian population was extremely limited. Phenobarbital 4 (7.0)
In this retrospective study, we determined the reasons for Carbamazepine 4 (7.0)
administration in patients hospitalized with SCAR, the Mexiletine 3 (5.3)
Antibiotics (antifungals) 4 (7.0)
clinical pattern of reactions and the drugs causing adverse
Cephalosporin (cefprozil, cefoxitin) 2
reactions in the biggest department of dermatology in Amoxicillin 1
China. Most notably, we aimed to examine the role of sys- Fluconazole 1
temic corticosteroids in SCAR treatment and explore the TCM (radix isatidis, propolis, herbs) 3 (5.3)
potential prognostic factors of SCAR. Indomethacin 2 (3.5)
Other drugs* 4 (7.0)
SJS/TEN
MATERIALS AND METHODS Carbamazepine 25 (26.0)
Antibiotics 15 (15.6)
Patient selection
Cephalosporin (cefotaxime, cefmetazole, 6
A retrospective review of electronic medical records was cefotiam, cefprozil, cefepime)
Levofloxacin 4
performed for all patients admitted to Department of
Metronidazole 2
Dermatology, Huashan Hospital as DRESS, SJS/TEN, and Amoxicillin 1
AGEP between January 2014 and December 2017. Clarithromycin 1
Inclusion criteria for this study required that patients met Erythromycin 1
the diagnostic guidelines set by the European Registry of Allopurinol 11 (11.5)
Severe Cutaneous Adverse Reactions (RegiSCAR)6 for TCM (berberine, bezoar, leonurus artemisia, 8 (8.3)
paraquat, radix isatidis, salvianolate, scolopendra,
DRESS and SJS/TEN or the modified European Study of sophora flavescens)
Severe Cutaneous Adverse Reactions (EuroSCAR) de- Methazolamide 5 (5.2)
scribed by Sidoroff et al.7 for AGEP. No patients were lost Compound paracetamol and amantadine 4 (4.2)
to follow-up in this retrospective study. Informed consent Edaravone 2 (2.0)
was obtained from all patients to use their electronic med- Phenytoin 2 (2.0)
Sulfasalazine 2 (2.0)
ical data. The study protocol was approved by the Ethical
Valaciclovir 2 (2.0)
Committee of Huashan Hospital (IRB no. KY2019-316). Valproate 2 (2.0)
Other drugs† 10 (10.4)
Assessment of drug causality
AGEP
The drugs responsible for SCAR were defined as pre- Antibiotics 8 (40.0)
6,7 Cephalosporin (cefaclor, cefotiam, cefepime) 3
viously described . The evaluation of drug causality was
Clindamycin 2
decided by a group of experienced dermatologists. In Azithromycin 1
brief, if a drug was used continuously for more than three Levofloxacin 1
months, withdrawn for more than 14 days, or with a latent Isepamicin 1
period less than three days, it would not be considered as TCM (notoginseng triterpenes, radix isatidis, 6 (30.0)
Cordyceps sinensis)
the culprit drug for DRESS or SJS/TEN6. However, latent
NSAIDS 2 (10.0)
period for AGEP could be less than three days (typically Paracetamol 1
within 48 hours or 24 hours for antibiotics)8. The “latent Meloxicam 1
period” referred to the period from drug initiation to Urea C 14 1 (5.0)
symptom onset. Moreover, previous use without a drug SCAR: severe cutaneous adverse reactions, DRESS: drug reaction
eruption history decreased suspicion, whereas an earlier with eosinophilia and systemic symptoms, TCM: traditional
reaction prioritized the drug. Hereafter, the remaining sus- chinese medicine, SJS: Stevens-Johnson syndrome, TEN: toxic
pected drugs were re-evaluated based on the literature epidermal necrolysis, AGEP: acute generalized exanthematous
review. For cases with several suspected drugs remained, pustulosis, NSAIDS: nonsteroidal anti-inflammatory drugs. *Com-
pound paracetamol and amantadine, flunarizine, oxcarbazepine,
those with high notoriety were firstly considered (listed in †
and phenytoin. Amlodipine, dabigatran, fentanyl, ossotide, para-
Table 1) and those with low notoriety were marked as cetamol, phenobarbital, pyrazinamide, rabeprazole, tetanus anti-
‘possible’ (not listed in Table 1). Moreover, the sensitizing toxin, and tropicamide.

546 Ann Dermatol

 SCARs in China

properties of different drugs were also taken into account. istration of IVIG in order to take into account the con-
founding factors. In terms of prognostic factor analysis of
Assessment of SCAR outcomes
SCAR, chi-squared test and one-way ANOVA were ap-
Clinical information with regards to demographic data, co- plied for univariate analysis. Then, the variables sig-
morbidities, latency, and duration from onset to maximum nificantly associated with prognosis of SCAR in univariate
BSA or BSA detachment (maximum BSA detachment for analysis and the variables of great clinical concerns were
SJS/TEN and maximum BSA skin lesion involvement for further included in Cox regression analysis and enter se-
DRESS and AGEP), maximum BSA or BSA detachment, lection was applied. The categorical variables were coded.
time from onset to pharmacotherapy, co-administration of The threshold for significance was set at p-value ＜0.05.
corticosteroids and intravenous immunoglobulin (IVIG) All statistical analyses were performed using IBM SPSS
was recorded and analyzed. Outcomes analyzed for phar- Statistics ver. 21.0 software (IBM Corp., Armonk, NY, USA).
macotherapy were progression of disease (defined as dura-
tion from the index day to maximum BSA or BSA detach- RESULTS
ment), severity of disease (maximum BSA or BSA detach-
Demographics
ment) and mortality. The 25th and 75th percentile of the
time length of the lesions withdrawal by 50% were calcu- As shown in Table 2, 173 SCAR patients were studied in
lated, and prognosis were defined as good when 50% of this study. SJS/TEN was the most prevalent SCAR observed
the lesions withdrew less than seven days. (55.5%, 96 cases), followed by DRESS (32.9%, 57 cases)
and AGEP (11.6%, 20 cases). Males were predominant
Statistical analysis
(1.48:1) in DRESS and females were predominant (0.54:1)
Linear regression analysis was applied to explore the asso- in AGEP, whereas the number of males and females were
ciation between the time from onset to corticosteroids similar for SJS/TEN. The mean period from drug initiation
treatment and progression of disease (duration from the in- to symptom onset is 27.4 days for DRESS, 14.3 days for
dex day to maximum BSA or BSA detachment) or severity SJS/TEN, and 6.2 days for AGEP. The most common un-
of disease (maximum BSA or BSA detachment), while derlying diseases justifying the use of drugs were hyper-
mortality analysis was based on logistic regression. Linear uricemia or gout in DRESS, infection in SJS/TEN and
regression models were adjusted for age, sex, and disease AGEP.
classification (SJS/TEN, DRESS or AGEP) and co-admin-

Table 2. Demographics
DRESS (n=57) SJS/TEN (n=96) AGEP (n=20)
Sex ratio (male/female) 1.48 (34/23) 1 (48/48) 0.54 (7/13)
Age (yr) 50.5 (32.3∼66) 51.5 (31.8∼65) 36 (31.3∼55)
Latent period (d)* 27.4±4.3 14.3±2.1 6.2±2.4
Underlying disease
Hyperuricemia/gout 23 (40.4) 11 (11.5) -
Infection† 8 (14.0) 27 (28.1) 9 (45.0)
Inflammatory disease‡ 8 (14.0) 2 (2.1) 2 (10.0)
Seizure/paralysis/spasm 7 (12.3) 15 (15.6) -
Pain§ 5 (8.8) 14 (14.6) 3 (15.0)
Others 5 (8.8) 19 (19.8) 3 (15.0)
Values are presented as ratio, median (interquartile range), mean±standard deviation, or number (%). DRESS: drug reaction with
eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized
exanthematous pustulosis, -: not applicable. *The period from drug initiation to symptom onset. †DRESS: respiratory infection (5 cases),
vaginitis (1 case), nasosinusitis (1 case), gastroenteritis (1 case). SJS/TEN: respiratory infection (8 cases), eye infection (5 cases), vaginitis
(3 cases), duodenal ulcer with Helicobacter pylori infection (2 cases), sepsis (2 cases), cervicitis (2 cases), skin infection (2 cases),
gastroenteritis (1 case), tuberculosis (1 case). AGEP: respiratory infection (2 cases), cholecystitis (1 case), gastroenteritis (2 cases), otitis
‡
(2 cases), nasosinusitis (1 case), urocystitis (1 case). DRESS: ankylosing spondylitis (4 cases), osteoarthritis (1 case), Crohn’s disease
(1 case), rheumatic arthritis (1 case), ulcerative colitis (1 case). SJS/TEN: ulcerative colitis (2 cases). AGEP: rheumatic arthritis (1 case),
periarthritis humeroscapularis (1 case). §DRESS: neuralgia (2 case), headache (1 case), post-surgery pain (1 case), pharyngalgia (1 case).
SJS/TEN: postherpetic neuralgia (5 cases), trigeminal neuralgia (3 cases), headache (3 cases), pharyngalgia (1 case), neuralgia (1 case),
and post-surgery pain (1 case). AGEP: pharyngalgia (3 cases).

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Table 3. Clinical characteristics

DRESS (n=57) SJS/TEN (n=96) AGEP (n=20)
Characteristic
n 95% CI n 95% CI n 95% CI
Fever ≥38.5oC 43 75 (63∼85) 80 83 (75∼89) 10 50 (30∼70)
Lymphadenopathy 36 63 (50∼74) 22 23 (16∼32) 2 10 (3∼30)
Atypical lymphocytes 11 19 (11∼31) 2 2 (0∼7) 1 5 (1∼24)
Leucocytosis 36 63 (50∼74) 27 28 (20∼38) 15 75 (53∼89)
Leucocytopenia 0 - 22 23 (16∼32) 0 -
Neutrophilia 27 47 (35∼60) 32 33 (25∼43) 16 80 (58∼92)
Lymphocytosis 0 - 0 - 0 -
Monocytosis 20 35 (24∼48) 15 16 (10∼24) 5 25 (11∼47)
Thrombocytosis 5 9 (4∼19) 7 7 (4∼14) 0 -
Thrombocytopenia 0 - 6 6 (3∼13) 1 5 (1∼24)
Eosinophilia 44 77 (65∼86) 9 9 (5∼17) 1 5 (1∼24)
Grade 1 11 19 (11∼31) 7 7 (4∼14) 1 5 (1∼24)
Grade 2 33 58 (45∼70) 2 2 (0∼7) 0 -
Extent of rash ＞50% 56 98 (91∼100) 95 99 (94∼100) 17 85 (64∼95)
Suggestive rash 52 91 (81∼96) 87 91 (83∼95) 20 100 (84∼100)
Facial edema 49 86 (75∼93) 46 48 (38∼58) 5 25 (11∼47)
Monomorphic maculopapular 16 28 (18∼41) 2 2 (0∼7) 0 -
Polymorphous maculopapular 40 70 (57∼80) 94 98 (93∼99) 20 100 (84∼100)
Urticarial 0 - 0 - 1 5 (1∼24)
Exfoliative 18 32 (21∼44) 88 92 (84∼96) 1 5 (1∼24)
Lichenoid 1 2 (0∼9) 0 - 0 -
Pustules 0 - 1 1 (0∼6) 20 100 (84∼100)
Purpura 15 26 (17∼39) 30 31 (23∼41) 4 20 (8∼41)
Infiltrated plaques 54 95 (86∼98) 41 43 (33∼53) 13 65 (54∼82)
Blisters 9 16 (9∼27) 74 77 (68∼84) 3 15 (5∼36)
Target-like lesions 4 7 (3∼17) 41 43 (33∼53) 4 20 (8∼41)
Eczema-like lesions 11 19 (11∼31) 3 3 (1∼9) 3 15 (5∼36)
Mucosal involvement 17 30 (20∼43) 90 94 (86∼97) 0 -
Mouth/throat/lips 12 21 (12∼33) 87 90 (83∼95) 0 -
Eyes 3 5 (2∼14) 53 55 (45∼65) 0 -
Genitalia 9 16 (9∼27) 69 72 (62∼80) 0 -
Other 1 2 (0∼9) 21 22 (15∼31) 0 -
Internal organ involvement* 56 98 (91∼100) 85 89 (81∼93) 6 30 (15∼52)
1 Organ involved 16 28 (18∼41) 36 38 (28∼47) 5 25 (11∼47)
2 Organs involved 30 53 (40∼65) 31 32 (24∼42) 1 5 (1∼24)
＞2 Organs involved 10 18 (10∼29) 18 19 (12∼28) 0 -
Liver 54 95 (86∼98) 69 72 (62∼80) 6 30 (15∼52)
Kidney 26 46 (33∼58) 53 55 (45∼65) 1 5 (1∼24)
Lung 12 21 (12∼33) 14 15 (9∼23) 0 -
Muscle/heart 9 16 (9∼27) 18 19 (12∼28) 1 5 (1∼24)
Spleen 5 9 (4∼19) 1 1 (0∼6) 0 -
Pancreas 1 2 (0∼9) 5 5 (2∼12) 0 -
Other 0 - 1 1 (0∼6) 0 -
Leucocytosis ＞10,000 U/L, Leucocytopenia ＜4,000 U/L, Neutrophilia ＞7,000 U/L, Lymphocytosis ＞4,000 U/L, Monocytosis ＞1,000
U/L, Thrombocytosis ＞400,000 U/L, Thrombocytopenia ＜100,000 U/L, Eosinophilia Grade 1: 700∼1,499 U/L, Eosinophilia Grade
2: ＞1,500 U/L. DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal
necrolysis, AGEP: acute generalized exanthematous pustulosis, -: stands for not applicable. *Liver: elevation of liver enzymes (twice
the normal value), kidney: elevation of creatinine (twice the normal value) or the occurrence of proteinuria or hematuria, lung:
inflammation or interstitial change on X-ray or computerized tomography (CT), muscle: elevation of creatine kinase (CK), heart: elevation
of CK-muscle/brain or myoglobin, spleen: splenomegaly reported on ultrasound or CT, pancreas: elevation of serum/uric amylase or
lipase, or pancreatic edema reported on CT.

548 Ann Dermatol

 SCARs in China

exposed to any medication according to the criteria of cul-

Clinical characteristics
prit drugs in RegiSCAR6 or modified EuroSCAR for AGEP7.
The clinical characteristics of the 173 SCAR patients were As for other SCAR cases, the summary of drug causality
summarized in Table 3. Fever ≥38.5oC was documented was presented in Table 1. In addition, we categorized all
in 75% of DRESS patients, 83% of SJS/TEN patients and SCAR cases by causative drugs into three groups: allopur-
50% of AGEP patients. Lymphadenopathy was observed inol group, carbamazepine group, and other causative
in 63% and 23% of DRESS and SJS/TEN patients respec- drugs group. Univariate analysis of the outcome measures
tively. Notably, 19% DRESS patients, 2% SJS/TEN patients showed difference in the severity of SCAR (p=0.031) but
and 5% AGEP patients showed peripheral atypical lym- no difference in the progression of SCAR among three
phocytes. Leucocytosis was found in 63% of DRESS, 28% causative drugs groups. Further two-two comparisons also
of SJS/TEN and 75% of AGEP patients. Leucocytopenia showed that the difference between allopurinol group and
was infrequent, with only 23% in SJS/TEN. Neutrophilia carbamazepine group (p=0.039) and the difference be-
was found in 47% of DRESS, 33% of SJS/TEN and 80% of tween carbamazepine group and other causative drugs
AGEP patients. Monocytosis was prevalent in DRESS pa- group were statistically significant (p=0.010). However,
tients (35%) but not in SJS/TEN (16%) and AGEP (25%). when stratified by disease types, causative drugs showed
Thrombocytosis was infrequent, with only 9% in DRESS difference only in the severity of SJS/TEN, whereas no dif-
and 7% in SJS/TEN patients. Thrombocytopenia was rare, ferences in the severity of DRESS or AGEP.
with only 6% in SJS/TEN. Eosinophilia, defined as an ab-
Treatment
solute eosinophil count ≥700 U/L, was present in 77% of
DRESS patients. While in SJS/TEN, only 9% of patients In our observational study, 56 DRESS patients (98.2%), 96
had an absolute eosinophil count ≥700 U/L. SJS/TEN patients (100.0%), and 20 AGEP patients (100.0%)
All patients experienced an acute skin eruption. 91% of received systemic corticosteroids. Intravenous methyl-
DRESS and SJS/TEN patients, and all of the AGEP patients prednisolone was given at 1∼1.5 mg/kg/d. Once the pro-
had suggestive rash. The criteria for suggestive rash was fa- gression of the disease was halted, which manifested as
cial edema or exfoliative dermatitis in DRESS, edematous no new lesions, Nikolsky sign turning negative, exudation
erythema, target-like lesions, mucosal involvement, flaccid improved, re-epithelialization and laboratory test results
blisters, and exfoliation in SJS/TEN, and sterile nonfolli- being stable, the dose of corticosteroids was tapered
cular pustules in AGEP6,9,10. The rash was a monomorphic promptly. Meanwhile, 43 DRESS patients (75.4%), 88
maculopapular in 28% of DRESS patients and only 2% of SJS/TEN patients (91.6%), and four AGEP patients (20.0%)
SJS/TEN patients, while in all other cases it was poly- received treatment with IVIG. IVIG was administered at
morphous, including variable combinations of other 0.4 g/kg/d for over 5 days. Univariate analysis of the out-
lesions. For example, DRESS patients usually had in- come measures showed that early use of systemic cortico-
filtrated plaques (95%), exfoliation (32%), purpura (26%), steroids was significantly and negatively related to the pro-
eczema-like lesions (19%), and blisters (16%). Whereas, gression of SCAR (p=0.000) and the severity of SCAR
SJS/TEN patients usually had exfoliation (92%), blisters (p=0.001). Further multivariate analysis also indicated the
(77%), target-like lesions (43%), and purpura (31%). Facial negative linear association of early use of systemic cortico-
edema was observed in 86% of DRESS patients, 48% of steroids and the progression (p=0.000) and the severity of
SJS/TEN patients and 25% of AGEP patients. Mucosal in- SCAR (p=0.01) (Table 4). Duration from onset to max-
volvement was recorded in 30% of DRESS patients and imum BSA or BSA detachment will be 0.858-day longer
94% of SJS/TEN patients. Most popular were oral lesions when the initiation of systemic corticosteroids was de-
(21% of DRESS patients and 90% of SJS/TEN patients). layed for 1 day (Table 4). It means later systemic cortico-
In terms of systemic involvement, most frequently the re- steroids use might prolong the duration of active stage
action affected the liver (95% of DRESS patients, 72% of SCAR, and it would take more time for SCAR patients to
SJS/TEN patients, and 30% of AGEP patients), followed by reach stable stage (no new lesions). Moreover, one-day
kidney (46% of DRESS patients, 55% of SJS/TEN patients, delay of the systemic corticosteroids use would increase
and 5% of AGEP patients) and lung (21% of DRESS pa- 19.2% of maximum BSA or BSA detachment (Table 4). In
tients and 15% of SJS/TEN patients). contrast, IVIG treatment did not statistically affect the pri-
mary outcomes of both the disease progression and
Causative drugs
severity. Among all 173 SCAR patients, none of them died
In this study, two DRESS patients (3.5%), eight SJS/TEN pa- during their stay in hospital, and only two DRESS patients
tients (8.3%), and three AGEP patients (15.0%) were not (3.5%), four SJS/TEN patients (4.2%) and no AGEP patient

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Table 4. Linear regression of SCAR progression and severity (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)
Unadjusted linear regression Adjusted linear regression
Standardized coefficients β p-value Standardized coefficients β p-value
Duration from onset to maximum BSA or BSA
detachment
Time from onset to corticosteroids treatment 0.857 0.000 0.858 0.000
Classification
AGEP 0 0
DRESS 0.285 0.02 0.022 0.758
SJS/TEN 0.158 0.195 0.04 0.599
Age (yr, linear) −0.002 0.952 0.011 0.790
Sex 0.019 0.802 −0.069 0.085
IVIG 0.166 0.029 0.052 0.274
Maximum BSA or BSA detachment
Time from onset to corticosteroids treatment 0.0244 0.001 0.192 0.010
Classification
AGEP 0 0
DRESS 0.14 0.232 0.099 0.442
SJS/TEN −0.212 0.07 −0.225 0.100
Age (yr, linear) −0.108 0.156 −0.097 0.180
Sex −0.015 0.846 −0.055 0.445
IVIG −0.047 0.542 0.026 0.759
Maximum BSA for AGEP and DRESS, and maximum BSA detachment for SJS/TEN. SCAR: severe cutaneous adverse reactions, DRESS:
drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN: toxic epidermal necrolysis, AGEP: acute
generalized exanthematous pustulosis, BSA: body surface area, IVIG: intravenous immunoglobulin.

died in the first three months after discharge. Both two Table 5. Logistic regression of mortality (complete case analysis:
DRESS patients died of lung infection. Three SJS/TEN pa- 57 DRESS, 96 SJS/TEN, and 20 AGEP)
tients died of multiple organ dysfunction syndrome, and Unadjusted logistic Adjusted logistic
one SJS/TEN patients died of lactic acidosis. For mortality regression regression
analysis, no statistical difference was revealed between OR (95% CI) OR (95% CI)
early and delayed systemic corticosteroids use (odds ratio Duration from onset to
[OR]: 1.01, 95% confidence interval [CI]: 0.95∼1.08) maximum BSA or
(Table 5). BSA detachment
Time from onset to 1.01 (0.95∼1.08) 1.02 (0.97∼1.09)
Prognostic factors of SCAR corticosteroids
treatment
Following risk factors were included in the regression Classification
model to analyze their associations with SCAR: disease DRESS 0.77 (0.14∼4.36) 0.77 (0.13∼4.72)
type, age, sex, lymphadenopathy, eosinophilia, mucosal SJS/TEN 1 1
involvement, internal organ involvement, interval from Age (yr, linear) 1.08 (1.02∼1.16) 1.08 (1.01∼1.16)
onset to standard treatment with adequate corticosteroids, Sex 1.85 (0.33∼10.41) 1.58 (0.26∼9.49)
combination therapy with IVIG, and causative drugs (Table Maximum BSA for AGEP and DRESS, and maximum BSA
6). Multivariate analysis showed disease type (p=0.035), detachment for SJS/TEN. DRESS: drug reaction with eosinophilia
lymphadenopathy (p=0.001), eosinophilia (p=0.019) and and systemic symptoms, SJS: Stevens-Johnson syndrome, TEN:
interval from onset to standard treatment with adequate toxic epidermal necrolysis, AGEP: acute generalized exanthe-
matous pustulosis, OR: odds ratio, CI: confidence interval, BSA:
corticosteroids (p=0.000) were the independent risk fac-
body surface area.
tors for the prognosis of SCAR. Patients with lymphaden-
opathy had longer time for 50% lesions’ withdrawal than
those with no lymphadenopathy (OR: 2.356, 95% CI: 1,500) and higher (＞1,500), high levels of eosinophilia
1.433∼3.875). Moreover, when we categorized eosino- proved to be a poor prognosis factor of SCAR, with 2-fold
philia into three groups: moderate (＜700), high (700∼ higher risks of longer lesions’ withdrawal time (high, OR:

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Table 6. Prognostic factors of SCAR (complete case analysis: 57 DRESS, 96 SJS/TEN, and 20 AGEP)
Univariate Multivariate
Covariate Exp (B)
p-value B p-value
(95% CI)
Disease type 0.001 0.035
SJS/TEN
AGEP 0.001 0.717 2.048（0.674∼6.224） 0.206
DRESS 0.046 −0.683 0.505（0.228∼1.116） 0.091
Sex 0.21 0.297 1.346（0.919∼1.971） 0.127
Age (yr) 0 1.000（0.989∼1.011） 0.975
Lymphadenopathy 0.025 0.857 2.356（1.433∼3.875） 0.001
Eosinophilia 0.021 0.019
＜700
700∼1,500 0.01 0.997 2.709（1.283∼5.721） 0.009
＞1,500 0.127 0.757 2.133（1.059∼4.296） 0.034
Mucosal involvement 0.001 0.207 1.231（0.635∼2.385） 0.539
Internal organ involvement 0.187 0.405
No organ involved
1 Organ involved 0.171 0.491 1.633（0.732∼3.644） 0.231
2 Organs involved 0.058 0.154 1.166（0.535∼2.540） 0.699
3 And more organs involved 0.046 0.193 1.213（0.523∼2.812） 0.653
Interval from onset to corticosteroids treatment −0.038 0.963（0.943∼0.983） 0.000
IVIG 0 −0.36 0.698（0.401~1.214） 0.203
Causative drugs 0.37 0.293
Allopurinol
Carbamazepine 0.161 0.706（0.391∼1.274） 0.248
Others 0.35 0.677（0.412∼1.113） 0.124
SCAR: severe cutaneous adverse reactions, DRESS: drug reaction with eosinophilia and systemic symptoms, SJS: Stevens-Johnson
syndrome, TEN: toxic epidermal necrolysis, AGEP: acute generalized exanthematous pustulosis, IVIG: intravenous immunoglobulin.

2.709, 95% CI: 1.283∼5.721; higher, OR: 2.133, 95% facial edema (86%), eosinophilia (77%), high fever (75%),
CI: 1.059∼4.296), compared with moderate eosinophilia leukocytosis (63%), and lymphadenopathy (63%) were
level. Furthermore, interval from onset to standard treat- characteristic for DRESS. As for SJS/TEN, the main features
ment with adequate corticosteroids was proved to be a next to the ubiquitous exanthema were mucosal involve-
protective factor for the prognosis of SCAR (OR: 0.963, ment (94%), internal organ involvement (89%), fever
95% CI: 0.943∼0.983). However, mucosal involvement, (83%), and neutrophilia (33%). As for AGEP, the main fea-
internal organ involvement, co-treatment with IVIG and tures were pustules (100%), neutrophilia (80%), leukocy-
SCAR causative drug types were not independent prog- tosis (75%), and fever (50%). Notably, our findings re-
nostic factors for SCAR. vealed that 46 SJS/TEN patients (48%) had facial edema,
which was quite different from the traditional concept that
DISCUSSION facial edema was the warning signal for DRESS and rarely
occurred in other SCAR6. We considered that diffuse er-
Previous studies showed conflicting results about the in- ythema on face in combination with mucosal involvement
cidence of SCAR in different genders. In our study, DRESS like conjunctivae or lips13 could manifest as facial edema
occurred more common in male than female. It might be in severe SJS/TEN cases. Additionally, 17 DRESS patients
due to the fact that 40.4% DRESS cases had underlying (30%) had mucosal involvement, which was similar as
hyperuricemia or gout, which is much more prevalent in previous reported3. Nine SJS/TEN patients (9%) had in-
men as well11. Whereas in SJS/TEN and AGEP, infection creased peripheral eosinophil counts, which highlighted
(28.1% for SJS/TEN and 45.0% for AGEP) was the most that eosinophilia could occur in SCAR other than DRESS14.
common underlying disease, which was consistent with Some studies even reported that eosinophilia was asso-
previous study12. ciated with poor SCAR outcomes15-17. Higher percentage
According to our data, internal organ involvement (98%), of lymphadenopathy in DRESS (63%) than other SCAR

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Z Xu, et al

was similar to previous studies, which would be explained treated with systemic steroids39-41. Here, we reveal that
by the potential activation of virus infections, such as early steroids therapy could alleviate the severity (p=0.01)
Epstein-Barr virus, cytomegalovirus or human herpesvirus and progression (p=0.000) of SCAR without influencing
6 in DRESS18-20. Six AGEP (30%) had internal organ in- the mortality rate. These results suggest that early short-
volvement, which was similar to previous studies that course steroids use is helpful in the initial phase manage-
AGEP-specific hepatitis, nephritis or pneumonia were rare ment of SCAR at least in a modern well-equipped tertiary
but sometimes occurred21,22. Thus, systemic investigations care hospital. Since more than 98.2% SCAR cases re-
were recommended for all SCAR types. ceived systemic steroids, we could not demonstrate the
Over the past few decades, important progress has been difference of outcomes with and without systemic steroids
made in understanding the pathogenesis of SJS/TEN, espe- use. Further studies with different therapy are required to
cially the role of human leukocyte antigen (HLA) alle- answer this question.
les23,24. Antiepileptic agents (phenobarbital, carbamaze- SCARs are associated with significant morbidity, mortality,
pine, phenytoin, and lamotrigine), minocycline, allopur- and socioeconomic costs. Predicting outcomes for each
inol, dapsone, and sulfonamides are the most frequently specific SCAR patient at an early stage would be ex-
reported causative drugs of DRESS25,26. In our study, the tremely helpful for physicians to formulate appropriate
most common culprit drug for DRESS was allopurinol. treatment strategy. However, very few clinical researches
HLA-B *58:01 has been reported to be associated with al- have focused on the prognostic factors of SCAR15-17,42,43.
lopurinol-induced SCAR27. As for carbamazepine, the According to our results, lymphadenopathy and eosino-
leading causative drug for SJS/TEN in our study, HLA-B philia were associated with a poor outcome. The role of
*15:02 was responsible for carbamazepine-induced eosinophilia in the outcomes of SCAR has been reported
SJS/TEN28, and HLA-A *31:01 showed a stronger correla- before15-17, while lymphadenopathy as a poor prognostic
tion with carbamazepine-induced DRESS29. Antibiotics factor for SCAR was reported for the first time. This can be
were the leading cause of AGEP in our findings, which explained by the potential activation of virus infections,
was also in agreement with previous reports30. However, such as Epstein-Barr virus, cytomegalovirus or human her-
further studies are required with regard to the limited pesvirus 618-20.
number of AGEP patients in our study. Notably, 5.3% Limitations of the study included the retrospective design
DRESS, 8.3% SJS/TEN, and 30.0% AGEP cases were and a predominance of Asian population. Since most
caused by traditional Chinese medicine (TCM) use. The SCAR patients in our study had received systemic cortico-
associated TCMs were radix isatidis, propolis, scolopen- steroids in combination with IVIG, further case-control
dra, salvianolate, sophora flavescens, berberine, paraquat, studies with larger sample size are required for more de-
Leonurus artemisia, bezoar, berberine, notoginseng tri- tailed research. In addition, there have been no universal
terpenes, Cordyceps sinensis, and Platycarya strobilacea. rules that could determine the causative drug of SCAR
Among those listed, only paraguat has been reported to with certainty, and the rule used in this study is imperfect
cause TEN31, and propolis has been reported to cause as well. Moreover, the long-term follow-up of SCAR pa-
32
fixed drug eruption . All other TCMs were newly tients post-discharge was lacking. However, due to the
reported. Considering the popular application of TCM fact that the ultimate prospective blinded study needed to
treatment in Asian cultures, connection between TCM and provide a more definitive answer to the questions about
SCAR needs to be further clarified. In our study, there steroid use in SCAR management is extremely difficult to
were still a small number of SCAR cases with no culprit do, our study is of significance in guiding clinical practice.
drugs, which was in accordance with previous studies that In conclusion, allopurinol, carbamazepine, and antibiotics
SCAR could attribute to exposures other than medications, were the most frequent implicated drugs for DRESS,
such as infection, foods or transplantation33. SJS/TEN, and AGEP respectively. Hyperuricemia or gout
Systemic corticosteroids have long been regarded as the was the most frequent cause of administration in DRESS,
mainstay treatment for SCAR. However it is still con- and infection was that in SJS/TEN and AGEP. Selection
troversial how much benefit patients would get from this and prescription of those drugs should be more
treatment. Some case series have concluded that the use cautiously. Additionally, early initiation of steroids might
of systemic steroids were beneficial in reducing morbidity help prevent the progression of skin lesions and decrease
and mortality34,35, whereas others suggesting minimal or the severity of skin lesions or skin detachment, but had no
no benefit in terms of outcome36-38. Some earlier ob- correlation with mortality. Lymphadenopathy and eosino-
servational studies even indicated an increased mortality philia were the independent poor prognostic factors of
and a higher frequency of complications for TEN patients SCAR. For SCAR patients with lymphadenopathy and eosi-

552 Ann Dermatol

 SCARs in China

nophilia, physicians may consider taking a more ag- Acute generalized exanthematous pustulosis (AGEP)--a
gressive therapeutic approach. clinical reaction pattern. J Cutan Pathol 2001;28:113-119.
8. Sidoroff A, Dunant A, Viboud C, Halevy S, Bavinck JN,
Naldi L, et al. Risk factors for acute generalized exanthe-
ACKNOWLEDGMENT matous pustulosis (AGEP)-results of a multinational case-
control study (EuroSCAR). Br J Dermatol 2007;157:989-996.
This work was supported by grants from Natural Science 9. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal
Foundation of China (No. 81573064 and 81472901) and necrolysis: part II. Prognosis, sequelae, diagnosis, differential
Shanghai Sailing Program (No. 19YF1404800). diagnosis, prevention, and treatment. J Am Acad Dermatol
We thank Prof. Xiaoqun Luo for her critical reading, and 2013;69:187.e1-16; quiz 203-204.
thank Dr. Shengan Chen and Xiaojin Wu for their ex- 10. Speeckaert MM, Speeckaert R, Lambert J, Brochez L. Acute
generalized exanthematous pustulosis: an overview of the
cellent technical assistance.
clinical, immunological and diagnostic concepts. Eur J
Dermatol 2010;20:425-433.
CONFLICTS OF INTEREST 11. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and
hyperuricemia in the US general population: the National
The authors have nothing to disclose. Health and Nutrition Examination Survey 2007-2008.
Arthritis Rheum 2011;63:3136-3141.
ORCID 12. Okamoto-Uchida Y, Nakamura R, Sai K, Imatoh T, Matsunaga
K, Aihara M, et al. Effect of infectious diseases on the
pathogenesis of Stevens-Johnson syndrome and toxic epi-
Zhongyi Xu, https://orcid.org/0000-0001-8158-0825
dermal necrolysis. Biol Pharm Bull 2017;40:1576-1580.
Jie Shen, https://orcid.org/0000-0003-2504-4491
13. Dodiuk-Gad RP, Chung WH, Valeyrie-Allanore L, Shear NH.
Yiwen Yang, https://orcid.org/0000-0003-0145-7283 Stevens-Johnson syndrome and toxic epidermal necrolysis:
Ruoyue Yuan, https://orcid.org/0000-0001-6970-8611 an update. Am J Clin Dermatol 2015;16:475-493.
Leihong Flora Xiang, https://orcid.org/0000-0003-2080-0550 14. Duong TA, Valeyrie-Allanore L, Wolkenstein P, Chosidow
Chengfeng Zhang, https://orcid.org/0000-0002-1302-5667 O. Severe cutaneous adverse reactions to drugs. Lancet
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