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

    References



    1. Hsu DY, Brieva J, Silverberg NB, et al. Morbidity and mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis in United States adults. J Invest Dermatol. 2016 Jul;136(7):1387-97.

    2. Sekula P, Dunant A, Mockenhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Invest Dermatol. 2013 May;133(5):1197-204.

    3. Yamane Y, Matsukura S, Watanabe Y, et al. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients–treatment and outcome. Allergol Int. 2016 Jan;65(1):74-81.

    4. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int. 2006 Mar;55(1):9-16.

    5. Chaby G, Maldini C, Haddad C, et al. Incidence of and mortality from epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) in France during 2003-16: a four-source capture-recapture estimate. Br J Dermatol. 2020 Mar;182(3):618-24.

    6. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol. 1997 Nov;24(11):726-9.

    7. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol. 2007 Feb;56(2):181-200.

    8. Frey N, Jossi J, Bodmer M, et al. The epidemiology of Stevens-Johnson syndrome and toxic epidermal necrolysis in the UK. J Invest Dermatol. 2017 Jun;137(6):1240-7.

    9. Kinoshita Y, Saeki H. A review of the pathogenesis of toxic epidermal necrolysis. J Nippon Med Sch. 2016;83(6):216-22.

    10. Harris V, Jackson C, Cooper A. Review of toxic epidermal necrolysis. Int J Mol Sci. 2016 Dec 18;17(12):2135.

    11. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med. 2011 Mar 24;364(12):1134-43.

    12. Bastuji-Garin S, Fouchard N, Bertocchi M,et al. SCORTEN: a severityof-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000 Aug;115(2):149-53.

    13. Guegan S, Bastuji-Garin S, Poszepczynska-Guigne E, et al. Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis. J Invest Dermatol. 2006 Feb;126(2):272-6.

    14. Heng YK, Lee HY, Roujeau JC. Epidermal necrolysis: 60 years of errors and advances. Br J Dermatol. 2015 Nov;173(5):1250-4.

    15. Torres-Navarro I, Briz-Redon A, Botella-Estrada R. Accuracy of SCORTEN to predict the prognosis of Stevens-Johnson syndrome/toxic epidermal necrolysis: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2020 Sep;34(9):2066-77.

    16. Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016. J

      Plast Reconstr Aesthet Surg.
      2016 Jun;69(6):e119-53.

    17. Roujeau JC, Chosidow O, Saiag P, et al. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol. 1990 Dec;23(6 Pt 1):1039-58.

    18. Chave TA, Mortimer NJ, Sladden MJ, et al. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol. 2005 Aug;153(2):241-53.

    19. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013 Aug;69(2):187.e1-16.

    20. Dodiuk-Gad RP, Olteanu C, Jeschke MG, et al. Treatment of toxic epidermal necrolysis in North America. J Am Acad Dermatol. 2015 Nov;73(5):876-7.e2.

    21. McGee T, Munster A. Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to regional burn center. Plast Reconstr Surg. 1998 Sep;102(4):1018-22.

    22. Palmieri TL, Greenhalgh DG, Saffle JR, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil. 2002 Mar-Apr;23(2):87-96.

    23. Schulz JT, Sheridan RL, Ryan CM, et al. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000 May-Jun;21(3):199-204.

    24. Le HG, Saeed H, Mantagos IS, et al. Burn unit care of Stevens Johnson syndrome/toxic epidermal necrolysis: A survey. Burns. 2016 Jun;42(4):830-5.

    25. Viard I, Wehrli P, Bullani R, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998 Oct 16;282(5388):490-3.

    26. Mockenhaupt M. The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011 Nov;7(6):803-13.

    27. Tsai TY, Huang IH, Chao YC, et al. Treating toxic epidermal necrolysis with systemic immunomodulating therapies: A systematic review and network meta-analysis. J Am Acad Dermatol. 2021 Feb;84(2):390-7.

    28. Metry DW, Jung P, Levy ML. Use of intravenous immunoglobulin in children with stevens-johnson syndrome and toxic epidermal necrolysis: seven cases and review of the literature. Pediatrics. 2003 Dec;112(6 Pt 1):1430-6.

    29. Liotti L, Caimmi S, Bottau P, et al. Clinical features, outcomes and treatment in children with drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis. Acta Biomed. 2019 Jan 29;90(3-S):52-60.

    30. Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol. 2012 Aug;167(2):424-32.

    31. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression.

      Arch Dermatol. 2003 Jan;139(1):33-6.

    32. Micheletti RG, Chiesa-Fuxench Z, Noe MH, et al. Stevens-Johnson syndrome/toxic epidermal necrolysis: a multicenter retrospective study of 377 adult patients from the United States. J Invest Dermatol. 2018

      Nov;138(11):2315-21.

    33. Brown KM, Silver GM, Halerz M, et al. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil. 2004 Jan-Feb;25(1):81-8.

    34. Shortt R, Gomez M, Mittman N, et al. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil.

      2004 May-Jun;25(3):246-55.

    35. Yeung CK, Lam LK, Chan HH. The timing of intravenous immunoglobulin therapy in Stevens-Johnson syndrome and toxic epidermal necrolysis. Clin Exp Dermatol. 2005 Sep;30(5):600-2.

    36. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin intoxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol. 2006 Apr;6(4):543-9.

    37. Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective

      study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008 Jan;58(1):33-40.

    38. Del Pozzo-Magana BR, Lazo-Langner A, Carleton B, et al. A systematic review of treatment of drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Popul Ther Clin Pharmacol.

      2011;18:e121-33.

    39. Lee HY, Lim YL, Thirumoorthy T, et al. The role of intravenous immunoglobulin in toxic epidermal necrolysis: a retrospective analysis of 64 patients managed in a specialized centre. Br J Dermatol. 2013 Dec;169(6):1304-9.

    40. Barron SJ, Del Vecchio MT, Aronoff SC. Intravenous immunoglobulin in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies. Int J Dermatol. 2015 Jan;54(1):108-15.

    41. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005 Oct 20;353(16):1711-23.

    42. Hirahara K, Kano Y, Sato Y, et al. Methylprednisolone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis: clinical evaluation

      and analysis of biomarkers. J Am Acad Dermatol. 2013 Sep;69(3):496-8.

    43. Zimmermann S, Sekula P, Venhoff M, et al. Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2017 Jun 1;153(6):514-22.

    44. Roujeau JC, Bastuji-Garin S. Systematic review of treatments for StevensJohnson syndrome and toxic epidermal necrolysis using the SCORTEN score as a tool for evaluating mortality. Ther Adv Drug Saf. 2011 Jun;2(3):87-94.

    45. Liu W, Nie X, Zhang L. A retrospective analysis of Stevens-Johnson syndrome/toxic epidermal necrolysis treated with corticosteroids. Int J Dermatol. 2016 Dec;55(12):1408-13.

    46. Power WJ, Ghoraishi M, Merayo-Lloves J, et al. Analysis of the acute ophthalmic manifestations of the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology.

      1995 Nov;102(11):1669-76.

    47. Roongpisuthipong W, Prompongsa S, Klangjareonchai T. Retrospective analysis of corticosteroid treatment in Stevens-Johnson syndrome and/or toxic epidermal necrolysis over a period of 10 years in Vajira

      Hospital, Navamindradhiraj University, Bangkok. Dermatol Res Pract. 2014;2014:237821.

    48. Chung WH, Wang CW, Dao RL. Severe cutaneous adverse drug reactions. J Dermatol. 2016 Jul;43(7):758-66.

    49. Emmel EA, Verweij CL, Durand DB, et al. Cyclosporin A specifically inhibits function of nuclear proteins involved in T cell activation. Science. 1989 Dec 22;246(4937):1617-20.

    50. Fernando SL. The management of toxic epidermal necrolysis. Australas J Dermatol. 2012 Aug;53(3):165-71.

    51. Downey A, Jackson C, Harun N, et al. Toxic epidermal necrolysis: review of pathogenesis and management. J Am Acad Dermatol. 2012 Jun;66(6):995-1003.

    52. Lee HY, Fook-Chong S, Koh HY, et al. Cyclosporine treatment for StevensJohnson syndrome/toxic epidermal necrolysis: retrospective analysis of a cohort treated in a specialized referral center. J Am Acad Dermatol. 2017 Jan;76(1):106-13.

    53. Valeyrie-Allanore L, Wolkenstein P, Brochard L, et al. Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2010 Oct;163(4):847-53.

    54. Ng QX, De Deyn M, Venkatanarayanan N, et al. A meta-analysis of cyclosporine treatment for Stevens-Johnson syndrome/toxic epidermal necrolysis. J Inflamm Res. 2018 Mar 28;11:135-42.

    55. Letko E, Papaliodis DN, Papaliodis GN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol. 2005 Apr;94(4):419-36.

    56. Reese D, Henning JS, Rockers K, et al. Cyclosporine for SJS/TEN: a case series and review of the literature. Cutis. 2011 Jan;87(1):24-9.

    57. Singh GK, Chatterjee M, Verma R. Cyclosporine in Stevens Johnson syndrome and toxic epidermal necrolysis and retrospective comparison with systemic corticosteroid. Indian J Dermatol Venereol Leprol. 2013

      Sep-Oct;79(5):686-92.

    58. Kirchhof MG, Miliszewski MA, Sikora S, et al. Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol. 2014 Nov;71(5):941-7.

    59. Mohanty S, Das A, Ghosh A, et al. Effectiveness, safety and tolerability of cyclosporine versus supportive treatment in Stevens-Johnson syndrome/

      toxic epidermal necrolysis: a record-based study. Indian J Dermatol Venereol Leprol. 2017 May-Jun;83(3):312-6.

    60. Poizeau F, Gaudin O, Le Cleach L, et al. Cyclosporine for epidermal necrolysis: absence of beneficial effect in a retrospective cohort of 174

      patients-exposed/unexposed and propensity score-matched mnalyses. J Invest Dermatol. 2018 Jun;138(6):1293-300.

    61. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol. 1985 Dec;121(12):1548-9.

    62. Bamichas G, Natse T, Christidou F, et al. Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher. 2002 Jun;6(3):225-8.

    63. Lissia M, Figus A, Rubino C. Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report. Br J Plast Surg. 2005 Jun;58(4):504-10.

    64. Szczeklik W, Nowak I, Seczynska B, et al. Beneficial therapeutic effect of plasmapheresis after unsuccessful treatment with corticosteroids in two patients with severe toxic epidermal necrolysis. Ther Apher Dial. 2010 Jun;14(3):354-7.

    65. Seczynska B, Nowak I, Sega A, et al. Supportive therapy for a patient with toxic epidermal necrolysis undergoing plasmapheresis. Crit Care Nurse. 2013 Aug;33(4):26-38.

    66. Kostal M, Blaha M, Lanska M, et al. Beneficial effect of plasma exchange in the treatment of toxic epidermal necrolysis: a series of four cases. J Clin

      Apher.
      2012;27(4):215-20.

    67. Yamada H, Takamori K. Status of plasmapheresis for the treatment of toxic epidermal necrolysis in Japan. Ther Apher Dial. 2008 Oct;12(5):355-9.

    68. Nassif A, Moslehi H, Le Gouvello S, et al. Evaluation of the potential role of cytokines in toxic epidermal necrolysis. J Invest Dermatol. 2004

      Nov;123(5):850-5.

    69. Paquet P, Nikkels A, Arrese JE, et al. Macrophages and tumor necrosis factor alpha in toxic epidermal necrolysis. Arch Dermatol. 1994 May;130(5):605-8.

    70. Gubinelli E, Canzona F, Tonanzi T, et al. Toxic epidermal necrolysis successfully treated with etanercept. J Dermatol. 2009 Mar;36(3):150-3.

    71. Hunger RE, Hunziker T, Buettiker U, et al. Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment. J Allergy Clin Immunol. 2005 Oct;116(4):923-4.

    72. Paradisi A, Abeni D, Bergamo F, et al. Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol. 2014 Aug;71(2):278-83.

    73. Scott-Lang V, Tidman M, McKay D. Toxic epidermal necrolysis in a child successfully treated with infliximab. Pediatr Dermatol. 2014 Jul-Aug;31(4):532-4.

    74. Pham CH, Gillenwater TJ, Nagengast E, et al. Combination therapy: etanercept and intravenous immunoglobulin for the acute treatment

      of Stevens-Johnson syndrome/toxic epidermal necrolysis. Burns. 2019 Nov;45(7):1634-8.

    75. Patmanidis K, Sidiras A, Dolianitis K, et al. Combination of infliximab and high-dose intravenous immunoglobulin for toxic epidermal necrolysis: successful treatment of an elderly patient. Case Rep Dermatol Med. 2012;2012:915314.

    76. Zarate-Correa LC, Carrillo-Gomez DC, Ramirez-Escobar AF, et al. Toxic epidermal necrolysis successfully treated with infliximab. J Investig Allergol Clin Immunol. 2013;23(1):61-3.

    77. Wojtkiewicz A, Wysocki M, Fortuna J, et al. Beneficial and rapid effect of infliximab on the course of toxic epidermal necrolysis. Acta Derm Venereol. 2008;88(4):420-1.

    78. Sachdeva M, Maliyar K, Ponzo MG. A systematic review of efficacy and safety of monotherapy and combination therapy with biologic for StevensJohnson syndrome and toxic epidermal necrolysis. J Cutan Med Surg. 2021 Nov-Dec;25(6):598-615.

    79. Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF-alpha antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest. 2018 Mar 1;128(3):985-96.

    80. Wolkenstein P, Latarjet J, Roujeau JC, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet. 1998 Nov 14;352(9140):1586-9.

    81. Zhang S, Tang S, Li S, et al. Biologic TNF-alpha inhibitors in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a systemic

      review. J Dermatolog Treat. 2020 Feb;31(1):66-73.

    82. Patel TK, Patel PB, Thakkar S. Comparison of effectiveness of interventions in reducing mortality in patients of toxic epidermal necrolysis: a network

      meta-analysis. Indian J Dermatol Venereol Leprol. 2021 Sep-Oct;87(5):628-44.

    83. Zhu QY, Ma L, Luo XQ, et al. Toxic epidermal necrolysis: performance of SCORTEN and the score-based comparison of the efficacy of corticosteroid therapy and intravenous immunoglobulin combined therapy in China. J Burn Care Res. 2012 Nov-Dec;33(6):e295-308.

    84. Torres-Navarro I, Briz-Redon A, Botella-Estrada R. Systemic therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis: a SCORTENbased systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2021 Jan;35(1):159-71.

    85. Yang L, Shou YH, Li F, et al. Intravenous immunoglobulin combined with corticosteroids for the treatment of Stevens-Johnson syndrome/toxic epidermal necrolysis: a propensity-matched retrospective study in China. Front Pharmacol. 2022 Jan 18;12:750173.

    86. Ao S, Gao X, Zhan J, et al. Inhibition of tumor necrosis factor improves conventional steroid therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis in a cohort of patients. J Am Acad Dermatol. 2022 Jun;86(6):1236-45.


    Purchase Article PDF for $1.99