Neha Singh, BS1 and Mariana Phillips, MD1,2

1Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
2Carilion Clinic Dermatology and Mohs Surgery, Roanoke, VA, USA

Conflict of interest: Mariana Phillips is an investigator for Castle Biosciences. Neha Singh has no disclosures.

Abstract: Toxic epidermal necrolysis (TEN) is an immune mediated, severe cutaneous adverse drug reaction characterized by epidermal detachment affecting greater than 30% body surface area. The mortality rate of TEN exceeds 20% and is usually caused by infection and respiratory compromise. Withdrawal of the causative drug, supportive care, and adjuvant therapy improve prognosis. Over the past decade, randomized controlled trials and meta-analyses have supported a role for cyclosporine, tumor necrosis factor alpha inhibitors, and combination therapy with intravenous immune globulin and corticosteroids. This review summarizes the medical management of TEN in adult patients.

Key Words: toxic epidermal necrolysis, TEN, Stevens-Johnson syndrome, SJS, intravenous immunoglobulin, IVIG, etanercept, cyclosporine, corticosteroids

Introduction

Toxic epidermal necrolysis (TEN) is a severe, life-threatening, adverse drug reaction characterized by widespread epidermal necrosis. The global mortality rate for TEN approaches 20-40%.1-5 Stevens-Johnson syndrome (SJS) and TEN are on the same spectrum and are clinically distinguished by percentage of body surface area detached. Patients are classified as SJS, SJS/TEN, or TEN if there is <10%, 10-30%, and >30% skin detachment, respectively.6

Initial manifestations of SJS and TEN include a prodrome of high fever and flu-like symptoms for 1-3 days followed by rapidly progressive mucocutaneous involvement. Ill-defined, targetoid, dusky macules that coalesce to form flaccid vesicles and bullae that eventually slough are typical. Blistering and detachment of the epidermis at the dermal epidermal junction can be induced with light pressure.7 Epidermal detachment may occur anywhere on the skin and mucosa, and commonly involves the ocular and respiratory epithelium. Complications include sepsis from loss of the skin barrier and respiratory compromise. Individuals with compromised immune systems (i.e., malignancies, human immunodeficiency virus (HIV), etc.) are at greater risk of developing TEN. Advanced age and comorbidities are associated with increased mortality.8

The exact pathogenesis of TEN remains unclear. It is traditionally considered to be a delayed type IV hypersensitivity immune reaction that results in cytotoxic CD8 T-cell mediated keratinocyte apoptosis.9-12

Drugs commonly associated with TEN include antibiotics like sulfonamides, tetracyclines, quinolones, as well as antiepileptics, antivirals, non-steroidal anti-inflammatory drugs (NSAIDs), and allopurinol.4 In the pediatric population, a TEN-like clinical presentation can be associated with Mycoplasma pneumoniae. Pharmacogenetic susceptibility to the development of TEN is present in certain populations. The human leukocyte antigen (HLA) B 15:02 confers an increased risk of TEN in Asian patients taking carbamazepine.10 Another allele, HLA-B 58:01, has been linked with allopurinol-induced TEN in European and Asian populations.11

The severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a well-validated specific predictor of mortality for patients with TEN.12-15 Aside from supportive care, the medical management of TEN is dependent upon the clinician’s critical appraisal of the available literature, and availability of various treatments.16-20 The primary purpose of this article is to provide a concise but comprehensive review on the medical management of SJS/TEN and TEN.

Treatment Modalities

Supportive Measures

Due to the rapid progression and complex nature of TEN, early intervention, close surveillance and multidisciplinary support are key to management. Patients may require observation in the intensive care and/or burn units.21-23 Supportive measures are aimed at maintaining thermoregulation and pain control, preventing major fluid loss, electrolyte imbalance, secondary infection, and scarring. Patients should be closely monitored for signs and symptoms of infection. Empiric antibiotics are associated with a poor prognosis and are therefore not indicated in the management of TEN. The most common organisms causing early infection are Staphylococcus aureus and Pseudomonas aeruginosa. Despite the importance in supportive measures, there is a lack of standardization among treating centers.24

Intravenous Immunoglobulin (IVIG)

Enthusiasm for IVIG in the treatment of TEN resulted from an initial study published by Viard et al., that showed IVIG preparations containing Fas-blocking antibodies could effectively inhibit the interaction of the Fas-ligand (FasL) with Fas-receptor, an established pathway of keratinocyte apoptosis.25 The same group reported an open, uncontrolled trial of 10 TEN patients who received 0.2-0.75 g/kg of IVIG per day for 4 consecutive days (Table 1). In all patients, disease progression ceased within 48 hours and rapid skin healing was noted.26 The popularity of IVIG for TEN increased since its introduction in 1998 and became the standard treatment for many years.

Aside from the pediatric population where IVIG is considered safe and effective, recent studies have challenged the use of IVIG in the management of TEN.27-29 Selected publications examining the use of IVIG for TEN are summarized in Table 1. Although IVIG was once considered the first-line treatment for SJS/TEN, a large meta-analysis concluded that administration of IVIG does not correlate with mortality reduction in multivariate regression analysis when adjusting for age, total body surface area involved, and delay in treatment compared to predicted mortality in adult patients.30 One prospective study examined the efficacy of a total dose of 2 g/kg IVIG (infused at a rate of 1 g/kg/day to 0.4 g/kg/day dependent on renal function) in 34 patients (9 with SJS, 5 with SJS/TEN, and 20 with TEN). No significant reduction in SCORTEN predicted mortality was noted (11 observed vs. 8.2 predicted). Disease progression was not interrupted by IVIG administration.31 Furthermore, a multicenter study that reviewed 377 SJS/TEN patients from 18 academic medical centers between 2000 and 2015 found no significant difference in mortality between treatment subgroups which included steroid monotherapy, IVIG monotherapy, and the combination of IVIG and corticosteroids.32 In one of the largest network meta-analyses to date, IVIG monotherapy showed no improvement in mortality rate when compared to supportive care.27 This network meta-analysis incorporated 67 studies published between 1999 to 2019 and included 2079 patients with SJS/TEN overlap or TEN. Regarding mortality rate and standardized mortality ratio, the surface under the cumulative ranking curve (SUCRA) score for IVIG rated below supportive care.27 Overall, the efficacy of IVIG in treating TEN remains uncertain and further prospective evaluation is warranted.

Table 1. Summary of studies reporting IVIG use in TEN*

Author Year Treatment Regimen # of Patients Reported Effects Study Design
Viard et al.25 1998 0.2-0.75 g/kg/day IVIG for 4 days n = 10 Reported benefit Case series
Brown et al.33 2004 0.4 g/kg/day for 4 days n = 24 No reported benefit Retrospective
Shortt et al.34 2004 0.2-0.75 g/kg/day for 4 days n = 16 Reported benefit Retrospective
Yeung et al.35 2005 1 g/kg/day for 3 days n = 6 Reported benefit Case series
French et al.36 2006 Cumulative dose IVIG > 2g/kg - Reported benefit Litaerature review
Schneck et al.37 2008 Median dose of 1.9 g/kg/day over 1 to 7 days n = 26 No reported benefit Retrospective
Del Pozzo-Magana et al.38 2011 IVIG 0.25-1.5 g/kg/ day for 5 days n = 57 Reported benefit Systematic review
Huang et al.30 2012 0.2-2 g/kg/day IVIG over 1 to 7 days n = 279 No reported benefit Systematic review and meta-analysis
Lee et al.39 2013 Cumulative IVIG dosage: o <3 g/kg o >3 g/kg n = 64 No reported benefit Retrospective
Barron et al.40 2015 Cumulative dosage of IVIG 1.6-3.85 g/kg n = 205 Reported benefit Systematic review
Micheletti et al.32 2018 IVIG alone, mean 1 g/kg/day for 3 days n = 133 No reported benefit Retrospective
Table 1. Summary of studies reporting IVIG use in TEN*
* The papers listed in each table reflects relevant data published within the last 30 years and includes the most cited papers encountered during this review.
Case reports were excluded.

Systemic Corticosteroid Therapy

Systemic steroids may be effective in treating SJS/TEN by the following mechanisms: 1) rapid acting: inhibiting the arachidonic acid cascade signaling pathway resulting in suppression of the inflammatory response and 2) slow acting: promoting transcription factors that suppress expression of inflammatory cytokines.41

The use of high-dose steroids in early SJS/TEN inhibits inflammation and decreases biomarkers of inflammation.42 Among 96 studies reviewed in a meta-analysis between the years 1990-2012, three studies suggested the benefit of corticosteroid treatment when compared to supportive care.43 Studies were variable in the duration of corticosteroids administration, most ranging from days 1-5 with an average of 3 days. A separate European multicenter retrospective study and meta-analysis of observational studies also highlighted the benefits of steroids.37,43

In contrast, several studies report no difference in prognosis between corticosteroid therapy and supportive care, due to the increased risk of infection caused by the immunosuppressive agent.2,44 More recently, a retrospective SCORTEN-based comparison was performed on patients who received low-doses (<2 mg/kg/day) and high-doses (>2 mg/kg/day) of either prednisone, or prednisone-equivalents of methylprednisolone, hydroprednisone, or dexamethasone (Table 2). Results revealed lower mortality rates in the low-dose steroid treatment group than those predicted by SCORTEN.45 In the high-dose steroid group, difference between the expected and actual mortality was not statistically significant; however, the actual mortality rate was 40% lower than the expected rate. A large retrospective study analyzing 366 patients for ocular sequelae found no benefit to steroid therapy.46

Table 2. Summary of studies reporting corticosteroid use in TEN

Author Year Treatment Regimen # of Patients Reported Effects Study Design
Hirahara et al.42 2013 Methylprednisolone 1000 mg/day for 3 days + oral prednisolone (0.8-1 mg/kg/day) or methylprednisolone 500 mg/day for 2 days n = 8 Reported benefit Retrospective
Roongpisuthipong et al.47 2014 Dexamethasone mean dose <15mg for an average of 5 days n = 87 No reported benefit Case series
Liu et al.45 2016 Low dose: <2 mg/kg/day High dose: >2 mg/kg/day (5 mg prednisone or 4 mg methylprednisolone or 5 mg hydroprednisone, or 0.75 dexamethasone). Duration of treatment ranged over 3 to 7 days depending on clinical response. n = 70 Reported benefit Retrospective
Table 2. Summary of studies reporting corticosteroid use in TEN

Currently, there is conflicting data on the benefit of corticosteroids in SJS/TEN. The beneficial effects of high-dose steroids must be weighed against the risk of complications including gastrointestinal (GI) bleeds, prolonged wound healing thus increasing the risk of infection, and increased mortality.

Cyclosporine

Cyclosporine, a calcineurin inhibitor, has been reported to have therapeutic benefit in the setting of SJS/TEN. This drug works by inhibiting activation of T cells and thus downstream mediators including FasL, nuclear factor-kB, and tumor necrosis factor alpha (TNF-α).48,49 Although less studied in comparison to other modalities discussed previously, cyclosporine has been shown to slow the progression of TEN and promote re-epithelialization.50,51

Several studies have shown favorable outcomes in patients receiving cyclosporine (Table 3). Lee et al., reported 24 patients who received 3 mg/kg/day of cyclosporine for 10 days. Three deaths occurred in contrast to the SCORTEN-predicted mortality of 5.9.52 Valeyrie-Allanore et al., investigated the same dosage of cyclosporine and found that rate of disease progression decreased; 62% of patients receiving cyclosporine experienced no disease progression at day 3.53 No deaths occurred in this study cohort which favorably contrasted with the SCORTEN-predicted mortality of 2.75.53 In a meta-analysis of 9 studies comparing cyclosporine with supportive care, a survival benefit for patients treated with cyclosporine was found.54 Cyclosporine is associated with hypertension and renal toxicity and both should be monitored during treatment.55 In one trial with 29 patients, only 26 were able to complete treatment due to side effects. Reported adverse reactions included neutropenia, leukoencephalopathy, and severe infection.53 Contraindications to cyclosporine include severe infections, internal malignancy, and renal dysfunction.54 Due to the small number of patients reported, further studies are needed to validate the efficacy of cyclosporine as a therapeutic agent for TEN.

Table 3. Summary of studies reporting cyclosporine use in TEN

Author Year Treatment Regimen # of Patients Reported Effects Study Design
Valeyrie-Allanore et al.53 2010 3 mg/kg/day for 10 consecutive days n = 29 Reported benefit Prospective open trial
Reese et al.56 2011 Initial dose of 5 mg/kg/day given in 2 divided doses. One patient was treated for 5 days. Others were discharged with 1 month taper. n = 4 Reported benefit Case series
Singh et al.57 2013 3 mg/kg/day for 7 consecutive days, followed by 7-day taper n = 11 Reported benefit Prospective open trial
Kirchhof et al.58 2014 Mean dose of 3-7 mg/kg/day for 3-5 days PO or 7 days IV n = 64 Reported benefit Case series
Lee et al.52 2017 3 mg/kg/day for 10 days then 2mg/kg/day for 10 days followed by 1 mg/kg/day for 10 days n = 24 Reported benefit Retrospective
Mohanty et al.59 2017 5 mg/kg/day for 10 days n = 19 Reported benefit Retrospective
Poizeau et al.60 2018 3 mg/kg/day for 10 days n = 95 No reported benefit Retrospective
Table 3. Summary of studies reporting cyclosporine use in TEN

Plasmapheresis

The mechanism of action of plasmapheresis involves clearing the circulating pathogenic metabolites including drugs, FasL, and TEN-induced cytokines from the patient’s blood. These sessions are typically carried out daily or every other day until patients show no signs of disease progression. The safety profile of plasmapheresis makes this therapeutic modality particularly attractive.50,51,61-65 Reported adverse events included transient paresthesias and urticaria. Most data on use of plasmapheresis in TEN come from case series and show improvement of disease progression (Table 4). In one case series involving 4 patients, those receiving plasmapheresis after unsuccessful treatment with corticosteroids and IVIG showed marked clinical improvement. Skin sloughing was interrupted and skin lesions began to heal after an average of 5.25 sessions.66 This treatment modality is not widely available, thus limiting its use.

Table 4. Summary of studies reporting plasmapheresis use in TEN

Author Year Treatment Regimen # of Patients Reported Effects Study Design
Yamada et al.67 2007 Plasmapheresis 1-6 sessions and double filtration plasmapheresis for 1-6 sessions n = 47 Reported benefit Literature review
Szczeklik et al.64 2010 Plasmapheresis for 8 sessions n = 2 Reported benefit Case series
Kostal et al.66 2012 Plasmapheresis for average of 5.25 ± 2.22 (range 3-8) sessions n = 4 Reported benefit Case series
Table 4. Summary of studies reporting plasmapheresis use in TEN

TNF-α Inhibitors

Skin lesions and blister fluid in TEN are known to contain high levels of TNF-α which prompted the use TNF-α inhibitors in patients with SJS/TEN.68,69 Both infliximab and etanercept have shown benefit.50,51,70-78

One case series published in 2014 included 10 patients who received a single dose of etanercept, 50 mg, subcutaneously (Table 5). All patients responded without any complications or adverse effects.72 The median time to healing was 8.5 days. Wang et al. studied etanercept 25 mg or 50 mg twice weekly compared with steroids in 96 SJS/TEN patients in a randomized controlled trial (RCT) and found that re-epithelialization occurred more quickly in the etanercept group (14 days for etanercept vs. 19 days for steroids). Additionally, etanercept was associated with a 9.4% reduction in SCORTEN predicated mortality and a lower actual mortality (8.3% with etanercept vs. 17.7% with steroid treatment) and fewer adverse events (GI hemorrhage).79 In the largest network metanalyses to date, etanercept was ranked the best among 10 treatments based on the SUCRA score for mortality rate.27 The SUCRA score is a metric used to evaluate which treatment in a network meta-analyses is likely to be the most efficacious. Although there are case reports to support the use of infliximab, this medication has not been as well studied.73

Table 5. Summary of studies reporting use of TNF-α inhibitors in TEN

Author Year Treatment Regimen # of Patients Reported Effects Study Design
Wolkenstein et al.80 1998 Thalidomide 400 mg for 5 days n = 22 No reported benefit RCT
Zarate-Correa et al.76 2013 Infliximab 300 mg x 1 dose n = 4 Reported benefit Case series
Paradisi et al.72 2014 Etanercept 50 mg x 1 dose n = 10 Reported benefit Case series
Wang et al.79 2018 Etanercept 25 mg or 50 mg twice a week n = 48 Reported benefit RCT
Zhang et al.81 2019 Monotherapy:
  • Infliximab 5 mg/kg as a single infusion
  • Etanercept 50 mg as a single injection
Second-line therapy following failed regimens of steroids or IVIG

Combination therapy:
  • Infliximab + steroids +/- IVIG
  • Etanercept + steroids +/- IVIG
 n = 91 Reported benefit Litaerature review
Table 5. Summary of studies reporting use of TNF-α inhibitors in TEN. RCT = randomized controlled trial

Combination Therapies

The combination of IVIG and corticosteroids has shown promise in patients with SJS/TEN.27,55,82 One retrospective study included 39 patients who received an initial dose of 1.5 mg/ kg/day of methylprednisolone for 3 to 5 days combined with a total dose of 2 g/kg IVIG for 5 days.83 Mortality rate with steroid monotherapy was 31% compared to 13% with combination therapy. Similarly, a network meta-analysis (2021) concluded that the combination of IVIG and corticosteroids was the only treatment that reduced the standardized mortality ratio with statistical significance.27 Additionally, following etanercept, the combination of corticosteroids and IVIG was calculated to have the second highest SUCRA score for mortality rate. These results were supported by another meta-analysis of 24 studies suggesting combination therapy (IVIG + steroids) had better therapeutic effect compared to either therapy alone.82 Additional studies support these findings.27,32,84,85 The combination of IVIG with etanercept was evaluated in 13 patients at a single institution from 2015 to 2018. There was no significant difference in mortality when compared to IVIG monotherapy. A systematic review supported the combination of corticosteroids and cyclosporine, although these findings warrant further investigation.39 The combination of TNF-α inhibitors with a steroid was investigated in 25 patients with SJS/TEN. Ten patients received methylprednisolone (equivalent to 1 to 1.5 mg/kg/day of prednisolone) and 15 patients received the steroid regimen in combination with 25 mg of etanercept twice weekly.86 Combination therapy significantly shortened the course of initial steroid treatment and time until skin re-epithelialization (median, 12 days) compared to steroid monotherapy (median, 16 days).

Conclusion

Over the past decade, there have been several meta-analyses detailing the efficacy of various treatments that serve to guide clinicians in the management of SJS/TEN and TEN.27,30,40,43,82,84 Early intervention is paramount. As soon as the diagnosis is considered, all potential offending drugs must be stopped. Transfer to a burn center and administration of systemic therapy should be considered. Management is heavily dependent on disease severity and rate of progression, patient comorbidities, available evidence, and physician experience.

Due to the complexity of the data and often conflicting results, no one treatment can be recommended at this time. Currently, there is not enough evidence to recommend IVIG or steroid monotherapy for adult patients with TEN. However, IVIG is still considered a safe and effective option for pediatric patients.28,29 Several network meta-analyses suggest that combination therapy with corticosteroids and IVIG, cyclosporine, and/or etanercept can reduce mortality of TEN.27,30,40,43,82,84 These treatment recommendations are summarized in Table 6.

Table 6. Summary of therapies for TEN that have been shown to be more efficacious than supportive measures in reducing mortality

Therapy Considerations
TNF-α inhibitors
  • Etanercept
  • Infliximab
    • Safe in pregnancy
    IVIG + corticosteroid
    • Safe in pregnancy
    IVIG
    • Most effective in pediatric patients
    Cyclosporine
    • US FDA pregnancy category C
    • Associated with renal toxicity
    • Cost effective in developing countries
    Table 6. Summary of therapies for TEN that have been shown to be more efficacious than supportive measures in reducing mortality

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