Toxic Epidermal Necrolysis: Past and Present Approaches

In This Article

Abstract and Introduction

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.

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.

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

*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.

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 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 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 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 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