Skip to main content
SpringerLink
Log in

Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis in the Era of Systems Medicine

  • Protocol
  • First Online:
Systems Medicine

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2486))

Abstract

Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe mucocutaneous bullous disorders characterized by widespread skin and mucosal necrosis and detachment, which are most commonly triggered by medications. Despite their rarity, these severe cutaneous adverse drug reactions will result in high mortality and morbidity as well as long-term sequela. The immunopathologic mechanisms is mainly cell-mediated cytotoxic reaction against keratinocytes leading to massive skin necrolysis. Subsequent studies have demonstrated that immune synapse composed of cytotoxic T cells with drug-specific human leukocyte antigen (HLA) class I restriction and T cell receptors (TCR) repertoire is the key pathogenic for SJS/TEN. Various cytotoxic proteins and cytokines such as soluble granulysin, perforin, granzyme B, interleukin-15, Fas ligand, interferon-γ, tumor necrosis factor-α have been as mediators involved in the pathogenesis of SJS/TEN. Early recognition and immediate withdrawal of causative agents, and critical multidisciplinary supportive care are key management of SJS/TEN. To date, there is yet to be a sufficient consensus or recommendation for the immunomodulants of the treatment in SJS/TEN. Systemic corticosteroids remain one of the most common treatment options for SJS/TEN, though the efficacy remain uncertain. Currently, there is increasing evidence showing that cyclosporine and TNF-α inhibitors decrease the mortality of SJS/TEN. Further multicenter double-blinded, randomized, placebo-controlled trials are required to confirm the efficacy and safety.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

APC:

Antigen-presenting cells

CTL:

Cytotoxic T lymphocyte

CTLA-4:

cytotoxic T-lymphocyte-associated protein 4

EMM:

erythema multiforme major

HLA:

Human leukocyte antigen

PD1:

programmed death-1

IFN-γ:

Interferon-γ

SCAR:

severe cutaneous adverse reaction

SJS:

Stevens–Johnson syndrome

TEN:

Toxic epidermal necrolysis

TCR:

T cell receptors

TNF-α:

Tumor necrosis factor-α

References

  1. Roujeau JC, Stern RS (1994) Severe adverse cutaneous reactions to drugs. N Engl J Med 331(19):1272–1285. https://doi.org/10.1056/NEJM199411103311906

    Article  CAS  PubMed  Google Scholar 

  2. Bastuji-Garin S, Rzany B, Stern RS et al (1993) Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129(1):92–96

    Article  CAS  PubMed  Google Scholar 

  3. Roujeau JC, Kelly JP, Naldi L et al (1995) Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 333(24):1600–1607. https://doi.org/10.1056/NEJM199512143332404

    Article  CAS  PubMed  Google Scholar 

  4. Chung WH, Wang CW, Dao RL (2016) Severe cutaneous adverse drug reactions. J Dermatol 43(7):758–766. https://doi.org/10.1111/1346-8138.13430

    Article  CAS  PubMed  Google Scholar 

  5. Schwartz RA, McDonough PH, Lee BW (2013) Toxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol 69(2):187.e181-116; quiz 203-184. https://doi.org/10.1016/j.jaad.2013.05.002

    Article  CAS  Google Scholar 

  6. Kamada N, Kinoshita K, Togawa Y et al (2006) Chronic pulmonary complications associated with toxic epidermal necrolysis: report of a severe case with anti-Ro/SS-A and a review of the published work. J Dermatol 33(9):616–622. https://doi.org/10.1111/j.1346-8138.2006.00142.x

    Article  PubMed  Google Scholar 

  7. Mockenhaupt M (2017) Epidemiology of cutaneous adverse drug reactions. Allergol Select 1(1):96–108. https://doi.org/10.5414/ALX01508E

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Harr T, French LE (2010) Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis 5:39. https://doi.org/10.1186/1750-1172-5-39

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sassolas B, Haddad C, Mockenhaupt M et al (2010) ALDEN, an algorithm for assessment of drug causality in Stevens–Johnson syndrome and toxic epidermal necrolysis: comparison with case–control analysis. Clin Pharmacol Ther 88(1):60–68

    Article  CAS  PubMed  Google Scholar 

  10. Wang YH, Chen CB, Tassaneeyakul W, Asian Severe Cutaneous Adverse Reaction C et al (2019) The medication risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in Asians: the major drug causality and comparison with the US FDA label. Clin Pharmacol Ther 105(1):112–120. https://doi.org/10.1002/cpt.1071

    Article  PubMed  Google Scholar 

  11. Lin CC, Chen CB, Wang CW et al (2020) Stevens-Johnson syndrome and toxic epidermal necrolysis: risk factors, causality assessment and potential prevention strategies. Expert Rev Clin Immunol 16(4):373–387. https://doi.org/10.1080/1744666X.2020.1740591

    Article  CAS  PubMed  Google Scholar 

  12. Chung WH, Shih SR, Chang CF et al (2013) Clinicopathologic analysis of coxsackievirus a6 new variant induced widespread mucocutaneous bullous reactions mimicking severe cutaneous adverse reactions. J Infect Dis 208(12):1968–1978. https://doi.org/10.1093/infdis/jit383

    Article  CAS  PubMed  Google Scholar 

  13. Canavan TN, Mathes EF, Frieden I et al (2015) Mycoplasma pneumoniae-induced rash and mucositis as a syndrome distinct from Stevens-Johnson syndrome and erythema multiforme: a systematic review. J Am Acad Dermatol 72(2):239–245. https://doi.org/10.1016/j.jaad.2014.06.026

    Article  PubMed  Google Scholar 

  14. Herold M, Nielson CB, Braswell D et al (2019) Clinicopathologic comparison of Rowell syndrome, erythema multiforme, and subacute cutaneous lupus erythematosus. J Am Acad Dermatol 81(6):1435–1438. https://doi.org/10.1016/j.jaad.2019.06.008

    Article  PubMed  Google Scholar 

  15. Macedo FI, Faris J, Lum LG et al (2014) Extensive toxic epidermal necrolysis versus acute graft versus host disease after allogenic hematopoietic stem-cell transplantation: challenges in diagnosis and management. J Burn Care Res 35(6):e431–e435. https://doi.org/10.1097/BCR.0000000000000040

    Article  PubMed  Google Scholar 

  16. White KD, Chung WH, Hung SI et al (2015) Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Allergy Clin Immunol 136(2):219–234; quiz 235. https://doi.org/10.1016/j.jaci.2015.05.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chung WH, Hung SI, Hong HS et al (2004) Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428(6982):486. https://doi.org/10.1038/428486a

    Article  CAS  PubMed  Google Scholar 

  18. Hung SI, Chung WH, Liou LB et al (2005) HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 102(11):4134–4139. https://doi.org/10.1073/pnas.0409500102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chessman D, Kostenko L, Lethborg T et al (2008) Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28(6):822–832. https://doi.org/10.1016/j.immuni.2008.04.020

    Article  CAS  PubMed  Google Scholar 

  20. Zhang FR, Liu H, Irwanto A et al (2013) HLA-B*13:01 and the dapsone hypersensitivity syndrome. N Engl J Med 369(17):1620–1628. https://doi.org/10.1056/NEJMoa1213096

    Article  CAS  PubMed  Google Scholar 

  21. Kaniwa N, Saito Y, Aihara M et al (2010) HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. Epilepsia 51(12):2461–2465. https://doi.org/10.1111/j.1528-1167.2010.02766.x

    Article  CAS  PubMed  Google Scholar 

  22. Kim SH, Lee KW, Song WJ et al (2011) Carbamazepine-induced severe cutaneous adverse reactions and HLA genotypes in Koreans. Epilepsy Res 97(1–2):190–197. https://doi.org/10.1016/j.eplepsyres.2011.08.010

    Article  CAS  PubMed  Google Scholar 

  23. Shi YW, Min FL, Qin B et al (2012) Association between HLA and Stevens-Johnson syndrome induced by carbamazepine in Southern Han Chinese: genetic markers besides B*1502? Basic Clin Pharmacol Toxicol 111(1):58–64. https://doi.org/10.1111/j.1742-7843.2012.00868.x

    Article  CAS  PubMed  Google Scholar 

  24. Hsiao YH, Hui RC, Wu T et al (2014) Genotype-phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: strength and clinical correlations. J Dermatol Sci 73(2):101–109. https://doi.org/10.1016/j.jdermsci.2013.10.003

    Article  CAS  PubMed  Google Scholar 

  25. Mockenhaupt M, Wang CW, Hung SI et al (2019) HLA-B*57:01 confers genetic susceptibility to carbamazepine-induced SJS/TEN in Europeans. Allergy 74(11):2227–2230. https://doi.org/10.1111/all.13821

    Article  PubMed  Google Scholar 

  26. Cheung YK, Cheng SH, Chan EJ et al (2013) HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese. Epilepsia 54(7):1307–1314. https://doi.org/10.1111/epi.12217

    Article  CAS  PubMed  Google Scholar 

  27. Hung SI, Chung WH, Liu ZS et al (2010) Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics 11(3):349–356. https://doi.org/10.2217/pgs.09.162

    Article  CAS  PubMed  Google Scholar 

  28. Chung WH, Chang WC, Lee YS, Taiwan Severe Cutaneous Adverse Reaction C, Japan Pharmacogenomics Data Science C et al (2014) Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA 312(5):525–534. https://doi.org/10.1001/jama.2014.7859

    Article  PubMed  Google Scholar 

  29. Locharernkul C, Loplumlert J, Limotai C et al (2008) Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 49(12):2087–2091. https://doi.org/10.1111/j.1528-1167.2008.01719.x

    Article  PubMed  Google Scholar 

  30. Su SC, Chen CB, Chang WC et al (2019) HLA alleles and CYP2C9*3 as predictors of phenytoin hypersensitivity in East Asians. Clin Pharmacol Ther 105(2):476–485. https://doi.org/10.1002/cpt.1190

    Article  CAS  PubMed  Google Scholar 

  31. Kaniwa N, Saito Y, Aihara M et al (2008) HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 9(11):1617–1622. https://doi.org/10.2217/14622416.9.11.1617

    Article  CAS  PubMed  Google Scholar 

  32. Kang HR, Jee YK, Kim YS et al (2011) Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet Genomics 21(5):303–307. https://doi.org/10.1097/FPC.0b013e32834282b8

    Article  CAS  PubMed  Google Scholar 

  33. Tassaneeyakul W, Jantararoungtong T, Chen P et al (2009) Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 19(9):704–709. https://doi.org/10.1097/FPC.0b013e328330a3b8

    Article  CAS  PubMed  Google Scholar 

  34. Mallal S, Nolan D, Witt C et al (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359(9308):727–732

    Article  CAS  PubMed  Google Scholar 

  35. Hetherington S, Hughes AR, Mosteller M et al (2002) Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359(9312):1121–1122. https://doi.org/10.1016/S0140-6736(02)08158-8

    Article  CAS  PubMed  Google Scholar 

  36. Wang CW, Tassaneeyakul W, Chen CB, Taiwan/Asian Severe Cutaneous Adverse Reaction C et al (2020) Whole genome sequencing identifies genetic variants associated with co-trimoxazole hypersensitivity in Asians. J Allergy Clin Immunol 147(4):1402–1412. https://doi.org/10.1016/j.jaci.2020.08.003

    Article  CAS  PubMed  Google Scholar 

  37. Nakamura R, Ozeki T, Hirayama N et al (2020) Association of HLA-A*11:01 with sulfonamide-related severe cutaneous adverse reactions in Japanese patients. J Invest Dermatol 140(8):1659–1662.e6. https://doi.org/10.1016/j.jid.2019.12.025

    Article  CAS  PubMed  Google Scholar 

  38. Kongpan T, Mahasirimongkol S, Konyoung P et al (2015) Candidate HLA genes for prediction of co-trimoxazole-induced severe cutaneous reactions. Pharmacogenet Genomics 25(8):402–411. https://doi.org/10.1097/FPC.0000000000000153

    Article  CAS  PubMed  Google Scholar 

  39. Kim SH, Kim M, Lee KW et al (2010) HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Pharmacogenomics 11(6):879–884. https://doi.org/10.2217/pgs.10.54

    Article  CAS  PubMed  Google Scholar 

  40. Lonjou C, Borot N, Sekula P et al (2008) A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 18(2):99–107. https://doi.org/10.1097/FPC.0b013e3282f3ef9c

    Article  CAS  PubMed  Google Scholar 

  41. Man CB, Kwan P, Baum L et al (2007) Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 48(5):1015–1018. https://doi.org/10.1111/j.1528-1167.2007.01022.x

    Article  CAS  PubMed  Google Scholar 

  42. Mehta TY, Prajapati LM, Mittal B et al (2009) Association of HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome among Indians. Indian J Dermatol Venereol Leprol 75(6):579–582. https://doi.org/10.4103/0378-6323.57718

    Article  PubMed  Google Scholar 

  43. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R et al (2013) Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol 149(9):1025–1032. https://doi.org/10.1001/jamadermatol.2013.4114

    Article  CAS  PubMed  Google Scholar 

  44. Roujeau JC, Huynh TN, Bracq C et al (1987) Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 123(9):1171–1173

    Article  CAS  PubMed  Google Scholar 

  45. Ciccacci C, Di Fusco D, Marazzi MC et al (2013) Association between CYP2B6 polymorphisms and Nevirapine-induced SJS/TEN: a pharmacogenetics study. Eur J Clin Pharmacol 69(11):1909–1916. https://doi.org/10.1007/s00228-013-1549-x

    Article  CAS  PubMed  Google Scholar 

  46. Chung WH, Hung SI, Chen YT (2007) Human leukocyte antigens and drug hypersensitivity. Curr Opin Allergy Clin Immunol 7(4):317–323. https://doi.org/10.1097/ACI.0b013e3282370c5f

    Article  CAS  PubMed  Google Scholar 

  47. Schneider CH, De Weck AL (1965) A new chemical spect of penicillin allergy: the direct reaction of penicillin with epsilon-amino-groups. Nature 208(5005):57–59

    Article  CAS  PubMed  Google Scholar 

  48. Pichler WJ (2002) Pharmacological interaction of drugs with antigen-specific immune receptors: the p-i concept. Curr Opin Allergy Clin Immunol 2(4):301–305

    Article  PubMed  Google Scholar 

  49. Wei CY, Chung WH, Huang HW et al (2012) Direct interaction between HLA-B and carbamazepine activates T cells in patients with Stevens-Johnson syndrome. J Allergy Clin Immunol 129(6):1562–1569.e1565. https://doi.org/10.1016/j.jaci.2011.12.990

    Article  CAS  PubMed  Google Scholar 

  50. Lin CH, Chen JK, Ko TM et al (2015) Immunologic basis for allopurinol-induced severe cutaneous adverse reactions: HLA-B*58:01-restricted activation of drug-specific T cells and molecular interaction. J Allergy Clin Immunol 135(4):1063–1065.e1065. https://doi.org/10.1016/j.jaci.2014.09.041

    Article  CAS  PubMed  Google Scholar 

  51. Illing PT, Vivian JP, Dudek NL et al (2012) Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486(7404):554–558. https://doi.org/10.1038/nature11147

    Article  CAS  PubMed  Google Scholar 

  52. Watkins S, Pichler WJ (2013) Sulfamethoxazole induces a switch mechanism in T cell receptors containing TCRVbeta20-1, altering pHLA recognition. PLoS One 8(10):e76211. https://doi.org/10.1371/journal.pone.0076211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ko TM, Chung WH, Wei CY et al (2011) Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol 128(6):1266–1276.e1211. https://doi.org/10.1016/j.jaci.2011.08.013

    Article  CAS  PubMed  Google Scholar 

  54. Chung WH, Pan RY, Chu MT et al (2015) Oxypurinol-specific T cells possess preferential TCR clonotypes and express granulysin in allopurinol-induced severe cutaneous adverse reactions. J Invest Dermatol 135(9):2237–2248. https://doi.org/10.1038/jid.2015.165

    Article  CAS  PubMed  Google Scholar 

  55. Ladell K, Hashimoto M, Iglesias MC et al (2013) A molecular basis for the control of preimmune escape variants by HIV-specific CD8+ T cells. Immunity 38(3):425–436. https://doi.org/10.1016/j.immuni.2012.11.021

    Article  CAS  PubMed  Google Scholar 

  56. Chung WH, Hung SI, Yang JY et al (2008) Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 14(12):1343–1350. https://doi.org/10.1038/nm.1884

    Article  CAS  PubMed  Google Scholar 

  57. Wang CW, Chung WH, Cheng YF et al (2013) A new nucleic acid-based agent inhibits cytotoxic T lymphocyte-mediated immune disorders. J Allergy Clin Immunol 132(3):713–722.e711. https://doi.org/10.1016/j.jaci.2013.04.036

    Article  CAS  PubMed  Google Scholar 

  58. Viard I, Wehrli P, Bullani R et al (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282(5388):490–493

    Article  CAS  PubMed  Google Scholar 

  59. Posadas SJ, Padial A, Torres MJ et al (2002) Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 109(1):155–161

    Article  CAS  PubMed  Google Scholar 

  60. Abe R, Shimizu T, Shibaki A et al (2003) Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol 162(5):1515–1520. https://doi.org/10.1016/S0002-9440(10)64284-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Voskoboinik I, Whisstock JC, Trapani JA (2015) Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol 15(6):388–400. https://doi.org/10.1038/nri3839

    Article  CAS  PubMed  Google Scholar 

  62. Deng A, Chen S, Li Q et al (2005) Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator. J Immunol 174(9):5243–5248

    Article  CAS  PubMed  Google Scholar 

  63. Abe R, Yoshioka N, Murata J et al (2009) Granulysin as a marker for early diagnosis of the Stevens-Johnson syndrome. Ann Intern Med 151(7):514–515

    Article  PubMed  Google Scholar 

  64. Weinborn M, Barbaud A, Truchetet F et al (2016) Histopathological study of six types of adverse cutaneous drug reactions using granulysin expression. Int J Dermatol 55(11):1225–1233. https://doi.org/10.1111/ijd.13350

    Article  CAS  PubMed  Google Scholar 

  65. Hsu HC, Thiam TK, Lu YJ et al (2016) Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients. Oncotarget 7(16):22257–22270. https://doi.org/10.18632/oncotarget.8076

    Article  PubMed  PubMed Central  Google Scholar 

  66. Chen CB, Kuo KL, Wang CW et al (2021) Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract 9(3):1327–1337.e1323. https://doi.org/10.1016/j.jaip.2020.09.048

    Article  CAS  PubMed  Google Scholar 

  67. Tewary P, Yang D, de la Rosa G et al (2010) Granulysin activates antigen-presenting cells through TLR4 and acts as an immune alarmin. Blood 116(18):3465–3474. https://doi.org/10.1182/blood-2010-03-273953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lanier LL (2005) NK cell recognition. Annu Rev Immunol 23:225–274. https://doi.org/10.1146/annurev.immunol.23.021704.115526

    Article  CAS  PubMed  Google Scholar 

  69. Morel E, Escamochero S, Cabanas R et al (2010) CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Allergy Clin Immunol 125(3):703–710, 710.e701-710.e708. https://doi.org/10.1016/j.jaci.2009.10.030

    Article  CAS  PubMed  Google Scholar 

  70. Su SC, Mockenhaupt M, Wolkenstein P et al (2017) Interleukin-15 is associated with severity and mortality in Stevens-Johnson syndrome/toxic epidermal necrolysis. J Invest Dermatol 137(5):1065–1073. https://doi.org/10.1016/j.jid.2016.11.034

    Article  CAS  PubMed  Google Scholar 

  71. Liu ZG (2005) Molecular mechanism of TNF signaling and beyond. Cell Res 15(1):24–27. https://doi.org/10.1038/sj.cr.7290259

    Article  CAS  PubMed  Google Scholar 

  72. Paquet P, Nikkels A, Arrese JE et al (1994) Macrophages and tumor necrosis factor alpha in toxic epidermal necrolysis. Arch Dermatol 130(5):605–608

    Article  CAS  PubMed  Google Scholar 

  73. Paul C, Wolkenstein P, Adle H et al (1996) Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 134(4):710–714

    Article  CAS  PubMed  Google Scholar 

  74. Viard-Leveugle I, Gaide O, Jankovic D et al (2013) TNF-alpha and IFN-gamma are potential inducers of Fas-mediated keratinocyte apoptosis through activation of inducible nitric oxide synthase in toxic epidermal necrolysis. J Invest Dermatol 133(2):489–498. https://doi.org/10.1038/jid.2012.330

    Article  CAS  PubMed  Google Scholar 

  75. Su SC, Mockenhaupt M, Wolkenstein P et al (2016) Interleukin-15 is associated with severity and mortality in Stevens-Johnson syndrome/toxic epidermal necrolysis. J Invest Dermatol 137(5):1065–1073. https://doi.org/10.1016/j.jid.2016.11.034

    Article  CAS  PubMed  Google Scholar 

  76. Nassif A, Moslehi H, Le Gouvello S et al (2004) Evaluation of the potential role of cytokines in toxic epidermal necrolysis. J Invest Dermatol 123(5):850–855. https://doi.org/10.1111/j.0022-202X.2004.23439.x

    Article  CAS  PubMed  Google Scholar 

  77. Tapia B, Padial A, Sanchez-Sabate E, Alvarez-Ferreira J et al (2004) Involvement of CCL27-CCR10 interactions in drug-induced cutaneous reactions. J Allergy Clin Immunol 114(2):335–340. https://doi.org/10.1016/j.jaci.2004.04.034

    Article  CAS  PubMed  Google Scholar 

  78. Correia O, Delgado L, Barbosa IL et al (2002) Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol 47(1):58–62

    Article  PubMed  Google Scholar 

  79. Paquet P, Paquet F, Al Saleh W et al (2000) Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis. Am J Dermatopathol 22(5):413–417

    Article  CAS  PubMed  Google Scholar 

  80. Caproni M, Torchia D, Schincaglia E et al (2006) Expression of cytokines and chemokine receptors in the cutaneous lesions of erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol 155(4):722–728. https://doi.org/10.1111/j.1365-2133.2006.07398.x

    Article  CAS  PubMed  Google Scholar 

  81. Goldinger SM, Stieger P, Meier B et al (2016) Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res 22(16):4023–4029. https://doi.org/10.1158/1078-0432.CCR-15-2872

    Article  CAS  PubMed  Google Scholar 

  82. Martens A, Wistuba-Hamprecht K, Geukes Foppen M et al (2016) Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res 22(12):2908–2918. https://doi.org/10.1158/1078-0432.CCR-15-2412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Laupacis A, Keown PA, Ulan RA et al (1982) Cyclosporin A: a powerful immunosuppressant. Can Med Assoc J 126(9):1041–1046

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee HY, Dunant A, Sekula P et al (2012) The role of prior corticosteroid use on the clinical course of Stevens–Johnson syndrome and toxic epidermal necrolysis: a case–control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies. Br J Dermatol 167(3):555–562. https://doi.org/10.1111/j.1365-2133.2012.11074.x

    Article  CAS  PubMed  Google Scholar 

  85. Law EH, Leung M (2014) Corticosteroids in Stevens-Johnson syndrome/toxic epidermal necrolysis: current evidence and implications for future research. Ann Pharmacother 49(3):335–342. https://doi.org/10.1177/1060028014560012

    Article  CAS  PubMed  Google Scholar 

  86. Dodiuk-Gad RP, Chung WH, Yang CH et al (2014) The 8th international congress on cutaneous adverse drug reactions, Taiwan, 2013: focus on severe cutaneous adverse reactions. Drug Saf 37(6):459–464. https://doi.org/10.1007/s40264-014-0165-8

    Article  PubMed  Google Scholar 

  87. Law EH, Leung M (2015) Corticosteroids in Stevens-Johnson syndrome/toxic epidermal necrolysis: current evidence and implications for future research. Ann Pharmacother 49(3):335–342. https://doi.org/10.1177/1060028014560012

    Article  CAS  PubMed  Google Scholar 

  88. Tristani-Firouzi P, Petersen MJ, Saffle JR et al (2002) Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 47(4):548–552. https://doi.org/10.1067/mjd.2002.127249

    Article  PubMed  Google Scholar 

  89. Huang YC, Li YC, Chen TJ (2012) The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol 167(2):424–432. https://doi.org/10.1111/j.1365-2133.2012.10965.x

    Article  CAS  PubMed  Google Scholar 

  90. Huang YC, Chien YN, Chen YT et al (2016) Intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. G Ital Dermatol Venereol 151(5):515–524

    PubMed  Google Scholar 

  91. Zimmermann S, Sekula P, Venhoff M et al (2017) Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol 153(6):514–522. https://doi.org/10.1001/jamadermatol.2016.5668

    Article  PubMed  PubMed Central  Google Scholar 

  92. Tsai TY, Huang IH, Chao YC et al (2021) Treating toxic epidermal necrolysis with systemic immunomodulating therapies: a systematic review and network meta-analysis. J Am Acad Dermatol 84(2):390–397. https://doi.org/10.1016/j.jaad.2020.08.122

    Article  CAS  PubMed  Google Scholar 

  93. Rajaratnam R, Mann C, Balasubramaniam P et al (2010) Toxic epidermal necrolysis: retrospective analysis of 21 consecutive cases managed at a tertiary centre. Clin Exp Dermatol 35(8):853–862. https://doi.org/10.1111/j.1365-2230.2010.03826.x

    Article  CAS  PubMed  Google Scholar 

  94. Valeyrie-Allanore L, Wolkenstein P, Brochard L, Ortonne N, Maître B, Revuz J, Bagot M, Roujeau JC (2010) Open trial of ciclosporin treatment for Stevens–Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 163(4):847–853. https://doi.org/10.1111/j.1365-2133.2010.09863.x

  95. Kirchhof MG, Miliszewski MA, Sikora S et al (2014) Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol 71(5):941–947. https://doi.org/10.1016/j.jaad.2014.07.016

    Article  CAS  PubMed  Google Scholar 

  96. Lee HY, Fook-Chong S, Koh HY et al (2017) Cyclosporine treatment for Stevens-Johnson syndrome/toxic epidermal necrolysis: retrospective analysis of a cohort treated in a specialized referral center. J Am Acad Dermatol 76(1):106–113. https://doi.org/10.1016/j.jaad.2016.07.048

    Article  CAS  PubMed  Google Scholar 

  97. González-Herrada C, Rodríguez-Martín S, Cachafeiro L et al (2017) Cyclosporine use in epidermal necrolysis is associated with an important mortality reduction: evidence from three different approaches. J Investig Dermatol 137(10):2092–2100. https://doi.org/10.1016/j.jid.2017.05.022

    Article  CAS  PubMed  Google Scholar 

  98. Poizeau F, Gaudin O, Le Cleach L et al (2018) Cyclosporine for epidermal necrolysis: absence of beneficial effect in a retrospective cohort of 174 patients exposed/unexposed and propensity score-matched analyses. J Investig Dermatol 138(6):1293–1300. https://doi.org/10.1016/j.jid.2017.12.034

    Article  CAS  PubMed  Google Scholar 

  99. Wolkenstein P, Latarjet J, Roujeau JC et al (1998) Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 352(9140):1586–1589. https://doi.org/10.1016/S0140-6736(98)02197-7

    Article  CAS  PubMed  Google Scholar 

  100. Kreft B, Wohlrab J, Bramsiepe I et al (2010) Etoricoxib-induced toxic epidermal necrolysis: successful treatment with infliximab. J Dermatol 37(10):904–906. https://doi.org/10.1111/j.1346-8138.2010.00893.x

    Article  PubMed  Google Scholar 

  101. Worsnop F, Wee J, Natkunarajah J et al (2012) Reaction to biological drugs: infliximab for the treatment of toxic epidermal necrolysis subsequently triggering erosive lichen planus. Clin Exp Dermatol 37(8):879–881. https://doi.org/10.1111/j.1365-2230.2012.04357.x

    Article  CAS  PubMed  Google Scholar 

  102. Gubinelli E, Canzona F, Tonanzi T et al (2009) Toxic epidermal necrolysis successfully treated with etanercept. J Dermatol 36(3):150–153. https://doi.org/10.1111/j.1346-8138.2009.00616.x

    Article  PubMed  Google Scholar 

  103. Paradisi A, Abeni D, Bergamo F et al (2014) Etanercept therapy for toxic epidermal necrolysis. J Am Acad Dermatol 71(2):278–283. https://doi.org/10.1016/j.jaad.2014.04.044

    Article  CAS  PubMed  Google Scholar 

  104. Didona D, Paolino G, Garcovich S et al (2016) Successful use of etanercept in a case of toxic epidermal necrolysis induced by rituximab. J Eur Acad Dermatol Venereol 30(10):e83–e84. https://doi.org/10.1111/jdv.13330

    Article  CAS  PubMed  Google Scholar 

  105. Chong I, Chao A (2017) Stevens-Johnson syndrome/toxic epidermal necrolysis and treatment with a biologic: a case report. Perm J 21:16-060. https://doi.org/10.7812/TPP/16-060

    Article  PubMed  PubMed Central  Google Scholar 

  106. Wang C-W, Yang L-Y, Chen C-B et al (2018) Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest 128(3):985–996. https://doi.org/10.1172/JCI93349

    Article  PubMed  PubMed Central  Google Scholar 

  107. Stern RS, Divito SJ (2017) Stevens-Johnson syndrome and toxic epidermal necrolysis: associations, outcomes, and pathobiology-thirty years of progress but still much to be done. J Invest Dermatol 137(5):1004–1008. https://doi.org/10.1016/j.jid.2017.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim D, Kobayashi T, Voisin B et al (2020) Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report. Nat Med 26(2):236–243. https://doi.org/10.1038/s41591-019-0733-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. White KD, Abe R, Ardern-Jones M et al (2018) SJS/TEN 2017: building multidisciplinary networks to drive science and translation. J Allergy Clin Immunol Pract 6(1):38–69. https://doi.org/10.1016/j.jaip.2017.11.023

    Article  PubMed  PubMed Central  Google Scholar 

  110. Chang WC, Abe R, Anderson P et al (2020) SJS/TEN 2019: from science to translation. J Dermatol Sci 98(1):2–12. https://doi.org/10.1016/j.jdermsci.2020.02.003

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei, and Keelung, Taiwan

    Chun-Bing Chen, Chuang-Wei Wang & Wen-Hung Chung

  2. Cancer Vaccine and Immune Cell Therapy Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan

    Chun-Bing Chen, Chuang-Wei Wang & Wen-Hung Chung

  3. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chun-Bing Chen & Wen-Hung Chung

  4. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chun-Bing Chen, Chuang-Wei Wang & Wen-Hung Chung

Authors
  1. Chun-Bing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chuang-Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-Hung Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Jane P.F. Bai

  2. School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA

    Junguk Hur

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Chen, CB., Wang, CW., Chung, WH. (2022). Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis in the Era of Systems Medicine. In: Bai, J.P., Hur, J. (eds) Systems Medicine. Methods in Molecular Biology, vol 2486. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2265-0_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-2265-0_3

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2264-3

  • Online ISBN: 978-1-0716-2265-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation