Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis

management,Prognosis and long term sequelae

Authors:Whitney A High, MDJean-Claude Roujeau, MDSection Editors:N Franklin

Adkinson, Jr, MDMoise L Levy, MDMaja Mockenhaupt, MD, PhDDeputy
Editor:Rosamaria Corona, MD, DSc
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Apr 2018. | This topic last updated: Nov
14, 2017.
What's New
Cyclosporine for Stevens-Johnson syndrome/toxic epidermal
necrolysis (November 2017)
Beyond supportive care, there are no established therapies for Stevens-
Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a severe and
often life-threatening drug reaction. Immunosuppressive or
immunomodulating therapies used in clinical practice include systemic
corticosteroids, intravenous immune globulins, and cyclosporine. None has
been adequately studied in randomized trials, but there is increasing
evidence that cyclosporine may slow the progression of SJS/TEN. In a
meta-analysis of observational studies including 134 patients with
SJS/TEN treated with cyclosporine, the observed mortality rate was
approximately 60 percent lower than that expected based upon the
SCORTEN prognostic score at admission [1]. We suggest cyclosporine in
addition to supportive care for the treatment of SJS/TEN. (See "Stevens-
Johnson syndrome and toxic epidermal necrolysis: Management,
prognosis, and long-term sequelae", section on 'Cyclosporine'.)
INTRODUCTION — Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) are severe mucocutaneous adverse reactions, most commonly
triggered by medications, characterized by fever and extensive necrosis and
detachment of the epidermis. SJS and TEN are considered a disease continuum
and are distinguished chiefly by severity, based upon the percentage of body
surface involved with skin detachment [1]:
●
SJS is the less severe condition, in which skin detachment is <10 percent of the
body surface (picture 1A-C). Mucous membranes are affected in over 90 percent
of patients, usually at two or more distinct sites (ocular, oral, and genital).

●
TEN involves detachment of >30 percent of the body surface area (picture 2A-D).
Mucous membranes are also involved in over 90 percent of cases.

●
SJS/TEN overlap describes patients with skin detachment of 10 to 30 percent of
body surface area. Mucous membranes are also involved in over 90 percent
of cases.

We will use the term "SJS/TEN" to refer collectively to SJS, TEN, and SJS/TEN
overlap.
The management, prognosis, and long-term sequelae of SJS/TEN are discussed in
this topic. The pathogenesis, clinical manifestations, and diagnosis are
discussed separately. (See "Stevens-Johnson syndrome and toxic epidermal
necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)
GENERAL PRINCIPLES — Patients with suspected SJS/TEN require
immediate in-hospital evaluation for diagnosis confirmation and evaluation of
severity, referral to the most appropriate health care setting (eg, intensive care
unit, burn unit, specialized dermatology unit, where present), and initiation of
supportive treatment. The management of these patients requires a
multidisciplinary approach by a team of clinicians experienced in treating
SJS/TEN. Our approach is discussed below. It is generally consistent with the
2016 United Kingdom guidelines for the management of SJS/TEN [2].
RAPID EVALUATION OF SEVERITY AND PROGNOSIS — Patients
suspected to have SJS and TEN should be admitted to the hospital. As soon as the
diagnosis of SJS or TEN has been established, the severity and prognosis of the
disease should be rapidly determined to define the appropriate medical setting for
management [2,3].
SCORTEN score — The prognosis of individual patients can be rapidly
evaluated on admission by applying a prognostic scoring system called SCORTEN
[4]. SCORTEN is based upon seven independent and easily measured clinical and
laboratory variables (table 1) and has been validated for use on days one and three
of hospitalization for SJS/TEN [5,6].
The SCORTEN score may be used to determine which clinical setting (intensive
therapy/burn unit or nonspecialized ward) is appropriate for the management of
the individual patient, as described below. The survival curves based upon the
SCORTEN score at admission (figure 1) may be helpful when discussing a
patient's prognosis with family members or medical staff [6]. However, it should
be noted that, due to progresses in the management of SJS/TEN patients in
specialized centers, including burn units, SCORTEN may overestimate the
mortality risk in those settings [7].
Referral to intensive therapy or burn unit — The decision to refer the patient to
an intensive care or burn unit should be made on a case-by-case basis, based upon
the extent of skin involvement and the presence of comorbidities. Patients with a
limited skin involvement, a SCORTEN score (table 1) of 0 or 1, and disease that is
not rapidly progressing may be treated in nonspecialized wards [8]. Patients with
more severe disease (skin detachment >30 percent of the body surface area) or a
SCORTEN score ≥2 should be transferred to intensive care units, burn units, or
specialized dermatology units, if available.
Several studies indicate that prognosis is better for patients transferred promptly to
a burn care unit or intensive care unit. In a retrospective multicenter review of 199
patients with TEN treated at burn care centers, the overall mortality was 32
percent compared with 51 percent among patients initially cared for in other
settings and transferred to a burn center more than one week after disease onset
[9].
PROMPT WITHDRAWAL OF CULPRIT DRUG — For patients with
suspected SJS and TEN induced by medications (table 2), early identification and
withdrawal of the offending agent may improve the prognosis. In a 10-year
observational study of 113 patients with TEN or SJS, early withdrawal of the
causative drug reduced the risk of death by 30 percent for each day before the
development of blisters and erosions (odds ratio [OR] 0.69; 95% CI 0.53-0.89)
[10]. However, exposure to drugs with long half-lives was associated with an
increased risk of death, independently from early or late withdrawal (OR 4.9; 95%
CI 1.3-18.9).
SUPPORTIVE CARE — The main principles of supportive care are the same as
for major burns and include wound care, fluid and electrolyte management,
nutritional support, temperature management, pain control, and monitoring or
treatment of superinfections [11-13]. (See "Treatment of superficial burns
requiring hospital admission".)
Ocular involvement requires immediate attention and care to reduce the risk of
permanent ocular sequelae.
Wound care — The extent of epidermal detachment should be evaluated daily or
every few days, depending upon the type of wound management, and may be
expressed as the percentage of body surface area that is involved (as for burns)
(figure 2). However, the evaluation of the affected skin area may be difficult in
patients presenting with small blisters scattered over large body areas.
The optimal approach to wound care in SJS/TEN has not been determined, and
different approaches are used at different centers [14-16].
●
Some centers surgically débride wounds and use whirlpool therapy to remove
necrotic epidermis [17]. Other centers use "antishear" wound care, in which the
detached skin is left in place to act like a biologic dressing [18]. In an
observational study, these two approaches (as practiced at expert centers) were
associated with equivalent rates of survival and re-epithelialization [18].

●
Nonadherent nanocrystalline gauze materials containing silver are increasingly
replacing petrolatum-impregnated gauze for the coverage of the denuded skin,
although controlled trials comparing the two have not been performed [19,20].
Nanocrystalline gauze dressings may be left in place for up to seven days,
decreasing the frequency of painful dressing changes. Biosynthetic skin substitutes
(eg, Biobrane, Aquacel AG, Suprathel) have also been used successfully [16,21].

●
Fluidized air beds are useful when the patient's backside is significantly denuded,
although these beds can make examination and care of those surfaces challenging
[22,23].

Fluids and nutrition — Fluid and electrolyte imbalances may occur due to
increased water loss from the denuded dermis, but replacement volumes are
approximately one-third lower than those needed for burn victims [24,25]. One
study of 21 patients with TEN and extensive skin loss treated at a burn center
estimated that fluid requirements during the first 24 hours may be accurately
determined by using the formula: 2 mL/kg of body weight multiplied by
percentage of body skin area skin detachment [26].
Room temperature should be increased to 30 to 32°C to prevent excessive caloric
expenditures due to epidermal loss [27]. Heated-air body warmers may also be
used.
Oral feeding, via a nasogastric tube if necessary, should be initiated as soon as
possible and continued throughout the acute phase of SJS/TEN [2,11]. Passage of
a nasogastric tube should be performed with great care to minimize damage to
affected mucous membranes.
Pain control — Cutaneous pain is common in patients with SJS/TEN and may be
severe in those with extensive skin detachment. Pain may also be exacerbated by
wound care procedures. Pain evaluation and administration of adequate analgesia
is thus a central component of the initial management of patients with SJS/TEN.
The principles of pain management in patients with SJS/TEN are similar to those
used in burn patients. (See "Management of burn wound pain and itching".)
The intensity of pain can be evaluated in older children and adults using a numeric
scale, which allows a patient to describe the pain on a scale of increasing severity,
typically from 0 to 10 (figure 3). This evaluation may be repeated every four hours
during the acute phase and guide the choice of the type and dose of medication
[28].
Mild pain (intensity <4) can be treated with nonopioid analgesics (eg,
paracetamol/acetaminophen, ibuprofen). Opioids are usually required for moderate
to severe pain (≥4). They act rapidly, are potent, and provide a dose-dependent
degree of sedation. For severe pain, the optimal route of administration is
intravenous, which provides faster pain relief and can be titrated to meet the
individual needs of the patient. Additional medication may be required during
patient mobilization or wound care procedures [28].
Prevention and treatment of infections — Patients with SJS/TEN are at high
risk of infection, and sepsis remains a prominent cause of death [27,29]. However,
prophylactic systemic antibiotics are not employed by the majority of specialists
and cannot be advised [9]. Instead, management involves the following elements:
●
Sterile handling is essential [24,30]. In intensive care or burn units, reverse-
isolation procedures are performed routinely, but they may not be necessary for
most patients with SJS treated in other settings. (See "Infection prevention:
Precautions for preventing transmission of infection".)

●
Antiseptic solutions containing octenidine, polyhexanide (eg, Octenisept,
Lavasept, Prontosan), or chlorhexidine or silver nitrate preparations may be used
for disinfection. Silver sulfadiazine should be avoided if SJS/TEN is suspected to
be caused by sulfonamides, but silver nitrate and silver-imbued nanocrystalline
gauze materials may be used safely [20]. (See 'Wound care' above.)

●
Repeated cultures of the skin, as well as blood, catheters, gastric, and urinary
tubes, should be obtained at 48-hour intervals [13,27]. (See "Infections and
antimicrobial resistance in the intensive care unit: Epidemiology and prevention".)

●
Signs of infection include visible superinfection of skin lesions, increase in the
quantity of bacteria cultured from a specific site, a sudden decrease in temperature,
or general deterioration [27]. Neutrophilia and increased levels of C-reactive
protein in patients with single organism-positive cultures from multiple sites may
indicate ongoing sepsis and require the prompt institution of systemic antibiotic
therapy [2,31].

●
Antibiotic choice should be based upon specific culture data whenever possible
[22]. Infections with gram-negative rods, especially Pseudomonas aeruginosa, are
particularly problematic [11,32]. (See "Pseudomonas aeruginosa skin and soft
tissue infections".)

Prevention of vulvovaginal sequelae — Early gynecologic examination should

be performed in all female patients with SJS/TEN with any signs or symptoms
referable to these sites. The goal of treatment of vaginal involvement is decreasing
the formation of adhesions and labial agglutination, as well as preventing vaginal
adenosis (presence of metaplastic cervical or endometrial glandular epithelium in
the vulva or vagina). (See "Stevens-Johnson syndrome and toxic epidermal
necrolysis: Pathogenesis, clinical manifestations, and diagnosis", section on
'Mucosal lesions'.)
Preventive strategies include the application of intravaginal corticosteroids,
regular use of soft vaginal molds (eg, Milex vaginal dilators), and menstrual
suppression during the acute phase of illness [33]. Moderate-potency topical
corticosteroids (group 4 (table 3)) can be applied intravaginally twice a day in
patients with ulcerative lesions, until resolution of the acute phase of illness.
Ointments are preferred to creams. Topical antifungal creams can be used in
conjunction with topical corticosteroids to prevent vaginal candidiasis. Soft
vaginal molds should be placed prophylactically as early as possible during the
acute phase of illness and used regularly until complete healing of ulcerative
lesions has occurred.
OCULAR MANAGEMENT
Evaluation — Immediate and ongoing attention to ocular involvement is
recommended to avoid permanent ocular complications [34]. A baseline
ophthalmologic consultation should be obtained soon after admission. (See 'Long-
term sequelae' below.)
The entire ocular surface should be carefully examined. Examination should
include fluorescein staining to document the presence of membranes and loss of
surface epithelium. The severity of ocular lesions can be graded using a simple
score [35]:
●
0 (none) – No ocular involvement
●
1 (mild) – Conjunctival hyperemia
●
2 (severe) – Either ocular surface epithelial defect or pseudomembrane formation
●
3 (very severe) – Both ocular surface epithelial defect and pseudomembrane
formation

Ophthalmic therapy — Because the eye inflammation can evolve quickly in the
first few days of the illness, daily evaluations and aggressive ophthalmic treatment
are indicated until it is clear that no worsening is occurring.
●
Saline rinses can be used to clean the eyes and eyelids and remove mucous and
inflammatory debris. Local ocular therapy should be started based upon the
severity of eye involvement [36].

●
For patients with no apparent eye involvement (grade 0), multiple daily lubrication
with preservative-free eye drops (artificial tears) or ointments is indicated.

●
For patients with conjunctival hyperemia (grade 1), ophthalmic preparations
containing topical corticosteroids and broad-spectrum antibiotics (eg,
moxifloxacin hydrochloride 0.5%) should be applied four to six times per day,
along with lubricants.

●
For patients with extensive sloughing of the bulbar conjunctiva and/or
pseudomembrane formation (grades 2 and 3), in addition to topical antibiotics,
corticosteroids, and lubricants, amniotic membrane transplantation (AMT)
performed early in the course of the disease (within 7 to 10 days) may prevent the
loss of visual acuity and cicatricial sequelae. Multiple procedures may be needed.

Cryopreserved amniotic membrane is commercially available in the United States

and Canada. In the United Kingdom, it can be obtained from the National Health
Service Blood and Transplant Tissue Services.
The use of AMT for the treatment of ocular involvement is supported by several
case series and one randomized trial [37-39]. In this trial, which included 25
patients (50 eyes), the eyes were randomized to receive AMT or standard medical
therapy [38]. The main endpoints were the maintenance of the best corrected
visual acuity (BCVA) and stable ocular surface (eg, absence of corneal haze,
limbal stem cell deficiency, symblepharon, ankyloblepharon, or lid-related
complications). After six months, the eyes treated with AMT had better BCVA,
tear film breakup time, and Schirmer test than eyes treated with medical therapy.
Conjunctival hyperemia persisted in 4 percent of the eyes treated with AMT
versus 44 percent of those treated with medical therapy. Corneal haze, corneal
vascularization and conjunctivalization, and symblepharon occurred in 44, 24, and
16 percent, respectively, of the eyes treated with medical therapy but in none of
those in the AMT group. Amniotic membrane sheets can be applied to the ocular
surface without sutures using a symblepharon ring, a technique avoiding general
anesthesia [40].
Role of systemic therapy — There is scarce and conflicting evidence on the role
of systemic adjunctive therapies in halting the ocular damage and improving the
visual outcome.
●
A Japanese retrospective study of 43 patients with SJS/TEN who were treated with
systemic corticosteroids, intravenous immune globulin (IVIG), or both; pulse
corticosteroids; or supportive care alone did not find any benefit of systemic
treatments in the ocular outcome, including best corrected visual acuity (BCVA)
and chronic ocular surface complications [41].

●
In another study, five patients with SJS or TEN with ocular complications during
the acute stage were treated within the first four days from disease onset with
intravenous pulses of methylprednisolone 500 or 1000 mg per day for three to four
days, along with 0.1% betamethasone solution, 0.1% betamethasone eye ointment,
or both five to eight times daily [42]. At one year, the BCVA was 20/20 or better
in all eyes. Epithelial defect, loss of limbal stem cells, conjunctivalization,
neovascularization, opacification, or keratinization were absent in all eyes; only
mild superficial punctate keratopathy was noted in five eyes.

ADJUNCTIVE THERAPIES — Beyond supportive care, there are no

established therapies for SJS and TEN [43-45]. Several immunosuppressive or
immunomodulating therapies have been used in clinical practice, including
systemic corticosteroids, intravenous immune globulin (IVIG), cyclosporine,
plasmapheresis, and anti-tumor necrosis factor (TNF) monoclonal antibodies.
None of these therapies have been adequately studied in randomized trials except
thalidomide, which was found to be harmful [46], and their use is based upon
clinical experience and local guidelines. However, there is increasing evidence
from multiple case series that cyclosporine may slow the progression of SJS/TEN.
(See 'Cyclosporine' below.)
The most commonly used therapies are discussed below.
Systemic corticosteroids — The use of systemic corticosteroids in patients with
SJS/TEN has not been evaluated in clinical trials and remains controversial [47].
Early observational studies indicated a higher frequency of complications and
increased mortality for patients with TEN treated in burn units with corticosteroids
[48-50].
Subsequent studies, including a large multicenter European study and a meta-
analysis, suggest that a short course of moderate to high dose systemic
corticosteroids (eg, prednisone 1 to 2 mg/kg per day for three to five days) may
not be harmful and may have a beneficial effect if given early in the course of the
disease (ie, within 24 to 48 hours of symptom onset) [43,51]. However, an updated
mortality analysis of the RegiSCAR cohort and a systematic review of case series
did not confirm a survival benefit for patients treated with systemic corticosteroids
[52,53].
●
In a retrospective analysis of 281 patients with SJS/TEN from France and
Germany enrolled in the EuroSCAR study, 159 patients received variable doses of
corticosteroids (ranging from 60 mg to 250 mg per day of prednisone equivalents),
75 IVIG (40 in association with corticosteroids), and 87 supportive care alone
[43]. The mortality rate was 18 percent in the corticosteroid group, 25 percent in
the IVIG group, and 25 percent in the supportive care group. The odds ratio (OR)
of death for patients treated with corticosteroids compared with patients treated
with supportive care alone was 0.6 (95% CI 0.3-1.0), suggesting a potential
benefit.

●
An analysis of 442 patients from the RegiSCAR cohort did not find a survival
advantage for patients treated with systemic corticosteroids compared with
patients treated with supportive therapy only (hazard ratio 1.3, 95% CI 0.8-1.9)
[52]. In a systematic review of 439 patients with SJS/TEN, the mortality rate was
22 percent among patients treated with systemic corticosteroids and 27 percent
among those treated with supportive measures only [53]. In both groups, mortality
rates were similar to those predicted by the SCORTEN score, without any
significant difference related to the type of treatment. (See 'SCORTEN score'
above.)

●
In a systematic review of treatment of SJS/TEN in children, including 31 case
series with 128 patients, 20 patients received either prednisolone or prednisone (1
mg/kg/day) or methylprednisolone (4 mg/kg/day) for five to seven days [54]. No
deaths were reported; complications occurred in five patients (mild skin infections
in three children and bronchiolitis in two).

●
In a Japanese series of 87 patients with SJS (n = 52) or TEN (n = 35) seen from
2000 to 2013, 84 were treated with systemic corticosteroids [55]. Steroid pulse
therapy was performed in approximately 90 percent of TEN patients. The authors
noted a remarkable decrease in mortality after 2006, from 4.5 to 0.0 percent in SJS
and from 22.2 to 5.3 percent in TEN, despite much higher predicted mortality rates
based upon SCORTEN. The authors felt that the improved survival was related to
the addition of plasmapheresis and/or immunoglobulin therapy to systemic
corticosteroid therapy for the treatment of TEN after 2007.

●
A 2017 meta-analysis using individual data from 1209 patients, of whom 367
received systemic corticosteroids in addition to supportive treatment, found that
corticosteroid treatment was associated with a decreased risk of death compared
with supportive treatment alone (OR 0.67, 95% CI 0.46-0.97) [51].

Although some studies suggest a potential benefit of systemic corticosteroids for

SJS/TEN, uncertainties remain regarding specific treatment modalities (eg, oral
high doses versus intravenous "pulse" bolus doses), treatment timing and duration,
and whether corticosteroids should be administered in combination with other
adjunctive therapies (eg, cyclosporine). In addition, since corticosteroids
theoretically increase the risk of sepsis and protein catabolism and decrease the
rate of epithelialization, their use in patients with extensive skin detachment is not
recommended.
Intravenous immune globulin — Data surrounding the use of IVIG for SJS/TEN
are limited and conflicting [56-61]. The use of IVIG was initially proposed based
upon the hypothesis that Fas ligand (FasL) was the main mediator of widespread
keratinocyte apoptosis in TEN and on the finding that high dose IVIG were able to
antagonize FasL effects [62]. However, it is now widely accepted that granulysin,
a cytotoxic protein found in cytotoxic T cells, is the most important mediator [63].
(See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis,
clinical manifestations, and diagnosis", section on 'Pathogenesis'.)
Most early studies involved the administration of 1 to 1.5 g/kg of IVIG in a single
infusion. Later reports, mostly small series of patients from single centers, favored
"high-dose" regimens of 2 to >4 g/kg [64-68]. However, subsequent studies,
including a large European cohort study, could not demonstrate a significant
survival advantage for patients treated with either high- or low-dose IVIG
compared with patients treated with supportive care only, as summarized below:
●
A review of case series with at least 9 patients evaluated the outcome of 156
patients (22 with SJS and 134 with TEN or SJS/TEN overlap) treated with IVIG
[57]. The mean total dose of IVIG ranged from 1.6 to 3.9 g/kg. Treatment was
started 3.5 to 9.2 days after the disease onset and given for two to four days. The
average mortality rate was 20.5 percent (range 0 to 42 percent), with higher rates
in centers where lower doses of IVIG were used or the time to treatment was
longer.

●
In a series of 281 patients with SJS/TEN from the EuroSCAR cohort study, 35
patients were treated with IVIG alone and 40 with IVIG plus systemic
corticosteroids [43]. The dose of IVIG ranged from 0.7 to 2.3 g/kg and was given
in one to seven days. The mortality rate was 34 percent in the group treated with
IVIG alone, 18 percent in the group treated with IVIG and corticosteroids, and 18
percent in a group of 87 patients treated with supportive measures alone.

●
In a systematic review of 439 patients with SJS/TEN, the mortality rate was 24
percent among patients treated with IVIG and 27 percent among those treated with
supportive measures only [53]. The observed mortality rate in the IVIG group was
slightly lower than that predicted by the SCORTEN score (24 versus 29 percent).
(See 'SCORTEN score' above.)

●
In a series of 64 cases of TEN and SJS/TEN (mean SCORTEN score 2.6) treated
with IVIG, the overall mortality rate was 31 percent [69]. Mortality was similar
among patients treated with <3 g/kg IVIG and those treated with ≥3 g/kg (31 and
26 percent, respectively).

●
A 2012 systematic review and meta-analysis of 17 studies including 113 patients
treated with IVIG and 130 with supportive care only found no difference in the
risk of death between the two groups (OR 1.00; 95% CI 0.58-1.75) [70]. However,
a subgroup analysis showed a statistically nonsignificant reduction in the mortality
risk for patients treated with high-dose IVIG (total dose ≥2 g/kg) compared with
those treated with <2 g/kg (OR 0.49; 95% CI 0.11-2.30).

●
In a retrospective study of 64 patients with SJS/TEN treated at a single institution
over 10 years, 35 patients were treated with IVIG (average total dose 3 g/kg), 15
patients with cyclosporine, 2 with both IVIG and cyclosporine, and 12 with
supportive care [71]. The mortality rate was 30 percent among patients treated
with IVIG and 6 percent among those treated with cyclosporine.

●
A 2015 meta-analysis of 13 studies of patients who received IVIG for SJS or TEN,
the severity of which was determined using the SCORTEN, found an overall
standardized mortality ratio (SMR, ratio between the number of observed and
expected deaths) of 0.81 (95% CI 0.62-1.08), with a nonsignificant difference in
SMR among patients treated with IVIG compared with those who did not receive
IVIG (SMR difference -0.32, 95% CI -0.77 to 0.12) [72]. However, a meta-
regression performed to determine the effect of IVIG dose on SMR found
significant reductions in SMR with increasing IVIG dose (≥2 g/kg).

●
A 2017 meta-analysis using individual data from 1209 patients, of whom 215
received IVIG in addition to supportive treatment, found that IVIG treatment was
not associated with a decreased risk of death compared with supportive treatment
alone (OR 0.99, 95% CI 0.64-1.54) [51].

In summary, there is little evidence to support the use of IVIG in SJS/TEN. IVIG
adverse effects include renal, hematologic, and thrombotic complications. The risk
for serious complications is increased in patients receiving high-dose IVIG, in
older patients, and in those with preexisting renal or cardiovascular disorders.
Severe hemolysis and nephropathy have been reported in SJS/TEN patients treated
with IVIG [73]. (See "Intravenous immune globulin: Adverse effects".)
Combined therapy — Systemic corticosteroids and IVIG have been administered
in combination to patients with SJS/TEN, but the data are too limited to draw any
firm conclusions.
●
In a prospective, nonrandomized study, 36 patients with TEN received low-dose
IVIG (0.2 to 0.5 g/kg) plus intravenous dexamethasone 0.1 to 0.3 mg/kg per day
tapered in one to two weeks or dexamethasone alone [74]. One death occurred in
the combined therapy group and three in the corticosteroid only group, whereas
the SCORTEN-predicted deaths were five in both groups.

●
In the EuroSCAR cohort study, 35 patients were treated with IVIG alone and 40
with IVIG plus systemic corticosteroids [43]. The dose of IVIG ranged from 0.7 to
2.3 g/kg and was given in one to seven days. The mortality rate was 34 percent in
the group treated with IVIG alone and 18 percent in the group treated with IVIG
and corticosteroids.

●
In a retrospective study of 55 patients with TEN, 39 were treated with IVIG 0.4
g/kg per day for five days plus methylprednisolone 1.5 mg/kg per day for three to
five days and 22 with methylprednisolone alone [75]. The mortality rate was 13
percent (5 of 39) among patients treated with combination therapy and 23 percent
(5 of 22) among those treated with corticosteroids alone.

Cyclosporine — There is increasing evidence from multiple case series, including

a large one from Spain, and two systematic reviews that cyclosporine given at the
dose of 3 to 5 mg/kg per day may slow the progression of SJS/TEN, in the absence
of significant toxicity [51,71,76-80]. The mechanism of action of cyclosporine in
SJS/TEN involves the inhibition of T cell activation, thus preventing the
production and release by cytotoxic T cells and natural killer cells of cytokines,
which play a critical role in the pathogenesis and propagation of SJS/TEN. (See
"Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical
manifestations, and diagnosis", section on 'Pathogenesis'.)
●
In an open trial including 29 patients with SJS/TEN treated with cyclosporin 3
mg/kg per day, all patients survived, despite an expected number of deaths of 2.75
based upon the SCORTEN score on admission [78]. Adverse effects, including
mild increase in serum creatinine, hypertension, and infection, occurred in 17
patients.

●
In a series of 44 consecutive patients with SJS/TEN hospitalized from 2011 to
2014, 24 received cyclosporine (3 mg/kg/day for 10 days tapered off over the
following 20 days) and 20 patients were treated supportively [79]. Three deaths
occurred in the cyclosporine group (7.2 expected on the basis of the SCORTEN
score) and six in the supportive treatment group (expected 5.9). However, these
results must be interpreted with caution because, despite a similar average
SCORTEN score in the two groups, patients treated with cyclosporine were
younger and had less comorbidities than patients treated supportively.
●
Cyclosporine at the dose of 3 mg/kg/day given in two divided doses for 7 to 21
days was successfully used in three pediatric patients (age 17 months to 8
years) [81]. All patients experienced rapid improvement, with near complete
resolution of skin and mucosal findings in 10 to 15 days.

●
In a study of 71 patients with SJS/TEN, of whom 49 were treated with
cyclosporine and 22 with other therapies, the observed mortality rates were 10 and
32 percent, respectively [80]. The expected mortality rates according to the
SCORTEN score at admission were 24 percent in the cyclosporine group
(observed-to-expected mortality rate ratio [MRR] 0.42, 95% CI 0.14-0.99) and 29
percent in the other therapies group (observed-to-expected MRR 1.09, 95% CI
0.44-2.25). In a meta-analysis including five additional observation studies, with a
total of 134 SJS/TEN patients treated with cyclosporine, the observed-to-expected
MRR was 0.41 (95% CI 0.21-0.80).

The results of these studies suggest that the administration of cyclosporine 3 to 5

mg/kg per day as early as possible in SJS/TEN may be beneficial. A possible
additional benefit from the association of cyclosporine with a short course of high-
dose corticosteroids needs further investigation [82].
Tumor necrosis factor inhibitors — In a few case reports, a single infusion of 5
mg/kg of the TNF-alpha inhibitor infliximab halted the progression of skin
detachment and induced a rapid re-epithelization of the denuded skin [83-86].
Etanercept, given in a single 50 mg subcutaneous injection, has been used
successfully in a small number of patients [87-89].
Plasmapheresis — Plasmapheresis has been reported to be beneficial in several
small series and case reports of TEN [90-94]. Removal of a toxin, such as a drug,
drug metabolite, or other cytotoxic mediator, has been proposed as a mechanism
of action. However, at least one series of patients demonstrated no difference in
mortality, length of stay in hospital, or time to re-epithelialization [95]. (See
"Therapeutic apheresis (plasma exchange or cytapheresis): Indications and
technology".)
Harmful agents — Thalidomide is a potent inhibitor of TNF-alpha. When this
cytokine was found to be potentially upregulated in TEN, thalidomide was
proposed as a potential therapy. Treatment with thalidomide was studied in a
randomized placebo-controlled trial of patients with TEN, but the trial was
stopped because of increased mortality among those given the active agent [46].
The exact mechanism by which thalidomide worsens TEN is not understood, but
its use is firmly contraindicated.
PROGNOSIS
Mortality — The overall mortality rate among patients with SJS and TEN is
approximately 25 percent, ranging from approximately 10 percent for SJS to more
than 30 percent for TEN [52,96,97]. In the United States, the mean adjusted
mortality rates between 2009 to 2012 were 4.8 percent for SJS, 19.4 percent for
SJS/TEN, and 14.8 percent for TEN [98]. Mortality is considerably lower in
children, ranging among centers from 0 to 9.5 percent [99-101].
Sepsis, acute respiratory distress syndrome, and multiple organ failure are the
most common causes of in-hospital death. Patients who develop acute renal failure
requiring renal replacement therapy have also an increased mortality risk [102].
Older age (>70 years) and presence of comorbidities, such as liver cirrhosis and
metastatic cancer, are also associated with an increased risk of death [103].
Disease severity (ie, the extent of cutaneous involvement) is the main risk factor
for mortality within 90 days of disease onset [52]. However, the risk of death
remains high beyond 90 days and up to one year after the onset of the reaction and
is mainly influenced by the patient's age and presence of comorbidities. Among
460 patients with SJS/TEN included in the European study RegiSCAR between
2003 and 2007, death rates of 23 and 34 percent were reported at six weeks and
one year after discharge, respectively [52].
Recurrence — Recurrence of SJS/TEN may occur if the patient is re-exposed to
the offending drug. Recurrent episodes due to structurally unrelated drugs or
infectious agents have also been reported [104-106]. The overall risk of recurrence
is unknown, although it seems to be higher in children with SJS/TEN associated
with infections.
●
In a series of 55 children with SJS/TEN, 10 children with SJS had recurrence up to
seven years after the index episode, and three experienced multiple recurrences
[104]. Recurrence was most often associated with Mycoplasma pneumoniae or
herpes simplex virus infection and occasionally with antiepileptic drugs.

●
In another retrospective study, nine children (all male) had 29 episodes of SJS or
incomplete SJS, with a median interval between episodes of 15 months (range 2 to
69 months) [105]. Involvement of one or more mucous membranes occurred in all
episodes, while rash was generally mild and present in approximately two-thirds
of the episodes. M. pneumoniae infection was documented in one-third of the
episodes; additional pathogens identified included Chlamydophila pneumoniae,
human metapneumovirus, parainfluenza virus type 2, and rhinovirus/enterovirus.

●
In a 10-year population-based cohort of 708 patients hospitalized for a first
episode of SJS or TEN, 7.2 percent of 581 survivors were hospitalized for a
second episode and 1.4 percent had multiple recurrences; lack of direct access to
medical records precluded information about medication exposures [107]. The
median time to first recurrence was 315 days.
Taken together, the results of these studies suggest that patients with SJS or, to a
lesser extent, with TEN have a high risk of recurrence after a first episode,
reflecting a long-lasting vulnerability or a genetic predisposition to severe drug
reactions. However, an overestimation of the recurrence rate due to the
misclassification of cases of erythema multiforme as SJS cannot be excluded. (See
"Pathogenesis, clinical features, and diagnosis of erythema multiforme".)
Long-term sequelae — Long-term sequelae include cutaneous, mucosal, ocular,
and pulmonary complications, which are increasingly reported as survival
improves [104,108,109]. Patients should be advised that uncommon eye disorders
can develop even years after the event and that new symptoms should trigger
prompt evaluation by an ophthalmologist.
●
Cutaneous sequelae are common and include postinflammatory hypo- or
hyperpigmentation, scarring, eruptive nevi, abnormal regrowth of nails, telogen
effluvium, and chronic pruritus [108,109]. Scarring may occur when
superinfection complicates re-epithelialization or following surgical interventions,
such as debridement of necrotic skin or skin grafting using staples directly into the
affected skin.

●
Ophthalmologic sequelae develop in approximately 50 to 90 percent of patients
with acute ocular involvement and include dry eye, photophobia, ingrown
eyelashes (trichiasis), neovascularization of the cornea, keratitis, symblepharon,
and corneal scarring leading to visual impairment and, rarely, blindness [108,110-
114]. These sequelae are mainly due to functional alteration of the conjunctival
epithelium and decreased lacrimal film, leading to recurrent inflammation and
scarring. In a series of 30 patients with acute ocular involvement, approximately
one-half developed chronic ocular diseases [113]. Disorders included ocular
surface failure due to loss of corneal epithelial stem cells, recurrent episodic
inflammation, scleritis, and progressive conjunctival cicatrization resembling
mucous membrane pemphigoid (see "Ocular cicatricial pemphigoid"). In some
patients, new ocular signs and symptoms appeared up to eight years after the acute
SJS/TEN. In a study of 54 patients with SJS or TEN, nearly 90 percent developed
chronic ocular sequelae six months or more after the initial presentation [114].
Although only 11 percent of patients had severe ocular involvement detected
during the acute phase, 17 percent developed late severe complications, including
trichiasis, mucocutaneous junction abnormalities, and extensive corneal opacities.

●
Oral and dental sequelae are not rare and include mouth discomfort, xerostomia,
gingival inflammation and synechiae, caries, and periodontal disease [115]. Severe
dental growth abnormalities, such as dental agenesia, root dysmorphia, root-
building abortion, and microdontia, may occur in children.
●
In women, long-term vulvovaginal and urinary sequelae include labial
agglutination, introital stenosis, vaginal dryness, dyspareunia, urinary retention,
and hematocolpos [22,33,116,117]. Vaginal adenosis also has been reported
[118,119].

●
Long-term pulmonary complications include chronic bronchitis/bronchiolitis with
obstructive changes (including bronchiolitis obliterans and bronchiolitis obliterans
organizing pneumonia), bronchiectasis, and obstructive disorders [120,121].
Pulmonary sequelae may also occur in asymptomatic patients. A series of 32
patients with SJS/TEN underwent pulmonary function tests (PFT) at a median
time of three months after the acute episode. Although only two patients had
dyspnea, abnormal PFT were demonstrated in more than half of the cases [122].
The most frequent PFT abnormality was a reduced carbon monoxide (CO)
diffusion, which persisted at 12 months in 8 of 10 patients. (See "Bronchiolitis in
adults" and "Clinical manifestations and diagnosis of bronchiectasis in adults".)

●
Long term psychologic complications and psychiatric disorders (eg, anxiety,
depression) and decreased health-related quality of life have been reported in
survivors of SJS/TEN [123].

FUTURE DRUG AVOIDANCE

Patient education — Patients who survive SJS and TEN attributed to a
medication must be educated about future avoidance and understand that re-
exposure to the culprit drug may be fatal. Relevant information should be
inscribed on a medical information bracelet or necklace and worn at all times. As
an alternative, relevant information from the patients' medical records should be
reported in an "allergy passport" that patients must carry with them at all times.
Patients should learn all the various names for the causative medication, be able to
report that they have a history of SJS or TEN, and be able to recognize closely-
related medications.
Future use of related medications — Recurrent SJS/TEN with readministration
of the culprit drug or closely chemically related agents is documented in multiple
case reports [124-126]. The risk of recurrent SJS/TEN with structurally distinct
agents (within the same therapeutic class of drugs) is unknown but probably very
low. As an example, patients with past SJS/TEN due to sulfamethoxazole should
avoid other anti-infectious sulfonamides (eg, sulfadiazine, sulfapyridine) but can
use thiazide diuretics or sulfonylurea-derived oral antidiabetics [127].
Patients with SJS/TEN caused by "aromatic" anticonvulsants (eg, phenytoin,
carbamazepine, phenobarbital) should be informed that other agents in the same
class may cause similar reactions in both the patient and their family members
(table 2) [128,129]. Although there are no data about the safety of nonaromatic
anticonvulsants (eg, valproate, succinimides, benzodiazepines, gabapentin) for
patients with a history of SJS/TEN induced by aromatic anticonvulsants, the risk
of SJS/TEN recurrence after exposure to a different class of anticonvulsants is
probably extremely low and certainly lower than the risk related to the absence of
antiepileptic treatment [130]. The pharmacology of antiepileptic agents is
reviewed in detail elsewhere. (See "Antiseizure drugs: Mechanism of action,
pharmacology, and adverse effects".)
Because human leukocyte antigen groups are associated with carbamazepine-,
phenytoin-, and allopurinol-induced SJS/TEN, family members of patients should
be alerted against the use of the same medication. (See "Stevens-Johnson
syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations,
and diagnosis", section on 'Genetic factors'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Stevens-Johnson syndrome and toxic
epidermal necrolysis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient
education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level,
and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)
●
Basics topic (see "Patient education: Stevens-Johnson syndrome and toxic
epidermal necrolysis (The Basics)")

SUMMARY AND RECOMMENDATIONS

●
Patients suspected to have Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) should be admitted to the hospital. The severity and prognosis of
the disease should be rapidly determined by using the SCORTEN score to define
the appropriate medical setting for management. (See 'Rapid evaluation of severity
and prognosis' above.)
●
For patients with extensive skin detachment and/or a SCORTEN score ≥2, we
suggest transfer to intensive therapy or burn unit if possible (Grade 2C). (See
'Referral to intensive therapy or burn unit' above.)

●
Early recognition and immediate withdrawal of any potentially causative agents
are critical first steps in the management of SJS/TEN. (See 'Prompt withdrawal of
culprit drug' above.)

●
Supportive care is the mainstay of treatment and includes wound care, fluid and
electrolyte management, nutritional support, ocular care, temperature
management, pain control, and monitoring or treatment of superinfections. (See
'Supportive care' above.)

●
The optimal approach to wound care has not been determined. Success has been
reported with both repeated debridement of exfoliating skin and "antishear" wound
care, in which the necrotic skin is left in place to act as a biologic dressing. (See
'Wound care' above.)

●
Ocular lesions require immediate attention and care. Specific interventions aimed
at preventing long-term ocular sequelae in severe cases with extensive sloughing
of the bulbar conjunctiva include the use of preservative-free corticosteroid eye
drops, coverage of the eye surface with cryopreserved amniotic membrane, and
use of scleral spacers. (See 'Ocular management' above.)

●
Because sepsis is the major cause of death, infection control measures, including
sterile handling, topical antiseptic agents, and surveillance cultures of possible
sites of superinfection, are important components of prevention. Prophylactic
systemic antibiotics are not utilized by the majority of burn centers, although
antimicrobials should be administered at the first sign of infection, and choice of
agent should be guided by specific culture data. (See 'Prevention and treatment of
infections' above.)

●
Beyond supportive care, we suggest using cyclosporine 3 to 5 mg/kg/day as
adjunctive therapy early in the course of the disease (ie, within 24 to 48 hours of
symptom onset) (Grade 2C). (See 'Cyclosporine' above.)
●
The role of systemic corticosteroids in the management of SJS/TEN remains
uncertain. Treatment modality (eg, oral versus intravenous "pulse" administration),
dose, timing, and duration have not been determined. (See 'Systemic
corticosteroids' above.)

●
We suggest not using intravenous immune globulin (IVIG) for SJS/TEN (Grade
2C). In several meta-analyses, no clear survival advantage has been found for
patients with SJS/TEN treated with IVIG. (See 'Intravenous immune globulin'
above.)

●
The overall mortality rate among patients with SJS/TEN is approximately 25
percent, ranging from approximately 10 percent for SJS to more than 30 percent
for TEN. Sepsis, acute respiratory distress syndrome, and multiple organ failure
are the most common causes of in-hospital death. Long-term sequelae involving
the skin and eyes are common among survivors. (See 'Mortality' above and 'Long-
term sequelae' above.)

ACKNOWLEDGMENT — We are saddened by the death of Milton H Nirken,

MD, who passed away in August 2017. UpToDate wishes to acknowledge Dr.
Nirken's past work as an author for this topic.
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