Skip to main content

Association of Early Systemic Corticosteroid Therapy with Mortality in Patients with Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis: A Retrospective Cohort Study Using a Nationwide Claims Database

Abstract

Background

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe dermatologic disorders with high mortality. The role of systemic corticosteroids as an adjunctive therapy for SJS or TEN remains controversial.

Objective

The aim of this study was to determine whether treatment with early systemic corticosteroids impacts the in-hospital mortality of patients hospitalized with SJS or TEN.

Methods

Using the Japanese Diagnosis Procedure Combination Database, a large nationwide inpatient administrative claims database, we identified inpatients aged ≥ 18 years who were admitted with SJS or TEN. Treatment with early systemic corticosteroids was defined as starting treatment with systemic corticosteroids within 2 days (day 0 or day 1) of admission. The primary outcome was in-hospital mortality. We examined the association between early systemic corticosteroids and in-hospital mortality using propensity score (PS) analyses.

Results

We identified 1846 eligible patients with SJS or TEN, including 793 patients with early systemic corticosteroid use at ≤ 2 mg/kg/day, 558 patients with early systemic corticosteroid use at > 2 mg/kg/day, and 495 patients without early corticosteroid use. PS matching created 235 pairs (> 2 mg/kg/day vs. controls) and 332 pairs (≤ 2 mg/kg/day vs. controls). Early systemic corticosteroid use was not significantly associated with lower in-hospital mortality by PS matching (> 2 mg/kg/day vs. controls: relative risk [RR] 0.83, 95% confidence interval [CI] 0.37–1.85; ≤ 2 mg/kg/day vs. controls: RR 0.61, 95% CI 0.28–1.36) and by inverse probability of treatment weighting (> 2 mg/kg/day vs. controls: RR 0.99, 95% CI 0.45–2.19; ≤ 2 mg/kg/day vs. controls: RR 0.65, 95% CI 0.29–1.47).

Conclusion

Early systemic corticosteroid therapy for patients with SJS or TEN was not associated with lower in-hospital mortality. Further studies are needed to define the effect of corticosteroids for patients with SJS or TEN.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Mockenhaupt M. The current understanding of Stevens–Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803–13. https://doi.org/10.1586/eci.11.66 (quiz 14–5).

    Article  PubMed  Google Scholar 

  2. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens–Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019–24.

    Article  Google Scholar 

  3. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med. 1994;331(19):1272–85. https://doi.org/10.1056/NEJM199411103311906.

    CAS  Article  PubMed  Google Scholar 

  4. Mahar PD, Wasiak J, Hii B, et al. A systematic review of the management and outcome of toxic epidermal necrolysis treated in burns centres. Burns. 2014;40(7):1245–54. https://doi.org/10.1016/j.burns.2014.02.006.

    Article  PubMed  Google Scholar 

  5. Dodiuk-Gad RP, Olteanu C, Chung WH, Shear NH. The 9th International Congress on Cutaneous Adverse Drug Reactions at the 23rd World Congress of Dermatology in Vancouver, 2015. Drug Saf. 2016;39(3):271–6. https://doi.org/10.1007/s40264-015-0390-9.

    Article  PubMed  Google Scholar 

  6. Dodiuk-Gad RP, Olteanu C, Jeschke MG, Cartotto R, Fish J, Shear NH. Treatment of toxic epidermal necrolysis in North America. J Am Acad Dermatol. 2015;73(5):876–877.e2. https://doi.org/10.1016/j.jaad.2015.08.008.

    Article  PubMed  Google Scholar 

  7. Wolkenstein P, Latarjet J, Roujeau J-C, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet. 1998;352(9140):1586–9. https://doi.org/10.1016/s0140-6736(98)02197-7.

    CAS  Article  PubMed  Google Scholar 

  8. Roujeau JC, Bastuji-Garin S. Systematic review of treatments for Stevens–Johnson syndrome and toxic epidermal necrolysis using the SCORTEN score as a tool for evaluating mortality. Ther Adv Drug Saf. 2011;2(3):87–94. https://doi.org/10.1177/2042098611404094.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF-alpha antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Investig. 2018;128(3):985–96. https://doi.org/10.1172/JCI93349.

    Article  PubMed  Google Scholar 

  10. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol. 2005;153(2):241–53. https://doi.org/10.1111/j.1365-2133.2005.06721.x.

    CAS  Article  PubMed  Google Scholar 

  11. Liu W, Nie X, Zhang L. A retrospective analysis of Stevens–Johnson syndrome/toxic epidermal necrolysis treated with corticosteroids. Int J Dermatol. 2016;55(12):1408–13. https://doi.org/10.1111/ijd.13379.

    CAS  Article  PubMed  Google Scholar 

  12. 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. https://doi.org/10.1155/2014/237821.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. 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;58(1):33–40. https://doi.org/10.1016/j.jaad.2007.08.039.

    Article  PubMed  Google Scholar 

  14. 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 Investig Dermatol. 2013;133(5):1197–204. https://doi.org/10.1038/jid.2012.510.

    CAS  Article  PubMed  Google Scholar 

  15. Yang Y, Xu J, Li F, Zhu X. Combination therapy of intravenous immunoglobulin and corticosteroid in the treatment of toxic epidermal necrolysis and Stevens–Johnson syndrome: a retrospective comparative study in China. Int J Dermatol. 2009;48(10):1122–8. https://doi.org/10.1111/j.1365-4632.2009.04166.x.

    CAS  Article  PubMed  Google Scholar 

  16. Schulz JT, Sheridan RL, Ryan CM, MacKool B, Tompkins RG. A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil. 2000;21(3):199–204.

    CAS  Article  Google Scholar 

  17. Dorafshar AH, Dickie SR, Cohn AB, et al. Antishear therapy for toxic epidermal necrolysis: an alternative treatment approach. Plast Reconstr Surg. 2008;122(1):154–60. https://doi.org/10.1097/PRS.0b013e3181773d5d.

    CAS  Article  PubMed  Google Scholar 

  18. Kim KJ, Lee DP, Suh HS, et al. Toxic epidermal necrolysis: analysis of clinical course and SCORTEN-based comparison of mortality rate and treatment modalities in Korean patients. Acta Derm Venereol. 2005;85(6):497–502. https://doi.org/10.1080/00015550510038232.

    CAS  Article  PubMed  Google Scholar 

  19. 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;153(6):514–22. https://doi.org/10.1001/jamadermatol.2016.5668.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hynes AY, Kafkala C, Daoud YJ, Foster CS. Controversy in the use of high-dose systemic steroids in the acute care of patients with Stevens–Johnson syndrome. Int Ophthalmol Clin. 2005;45(4):25–48.

    Article  Google Scholar 

  21. Creamer D, Walsh SA, Dziewulski P, et al. U.K. guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults 2016. Br J Dermatol. 2016;174(6):1194–227. https://doi.org/10.1111/bjd.14530.

    CAS  Article  PubMed  Google Scholar 

  22. Kinoshita Y, Saeki H. A review of toxic epidermal necrolysis management in Japan. Allergol Int. 2017;66(1):36–41. https://doi.org/10.1016/j.alit.2016.06.001.

    Article  PubMed  Google Scholar 

  23. The Japanese Guideline Committee on Erythema Multiforme Major. Guidelines for the management of Stevens–Johnson syndrome and toxic epidermal necrosis. Jpn J Dermatol. 2016;126(9):1637–85 (in Japanese).

    Google Scholar 

  24. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167(4):492–9. https://doi.org/10.1093/aje/kwm324.

    Article  PubMed  Google Scholar 

  25. Mager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics. J Clin Pharmacol. 2003;43(11):1216–27. https://doi.org/10.1177/0091270003258651.

    CAS  Article  PubMed  Google Scholar 

  26. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34(28):3661–79. https://doi.org/10.1002/sim.6607.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Austin PC. The performance of different propensity-score methods for estimating differences in proportions (risk differences or absolute risk reductions) in observational studies. Stat Med. 2010;29(20):2137–48. https://doi.org/10.1002/sim.3854.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hernan MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiology. 2000;11(5):561–70.

    CAS  Article  Google Scholar 

  29. Su P, Aw CWD. Severe cutaneous adverse reactions in a local hospital setting: a 5-year retrospective study. Int J Dermatol. 2014;53(11):1339–45. https://doi.org/10.1111/ijd.12118.

    Article  PubMed  Google Scholar 

  30. Araki Y, Sotozono C, Inatomi T, et al. Successful treatment of Stevens–Johnson syndrome with steroid pulse therapy at disease onset. Am J Ophthalmol. 2009;147(6):1004–1011.e1. https://doi.org/10.1016/j.ajo.2008.12.040.

    CAS  Article  PubMed  Google Scholar 

  31. Kardaun SH, Jonkman MF. Dexamethasone pulse therapy for Stevens–Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87(2):144–8. https://doi.org/10.2340/00015555-0214.

    CAS  Article  PubMed  Google Scholar 

  32. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Investig Dermatol. 2000; 115(2):149–53. https://doi.org/10.1046/j.1523-1747.2000.00061.x.

    CAS  Article  PubMed  Google Scholar 

  33. Bastuji-Garin S, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clinical classification of cases of toxic epidermal necrolysis, Stevens–Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92–6.

    CAS  Article  Google Scholar 

  34. Yamana H, Moriwaki M, Horiguchi H, Kodan M, Fushimi K, Yasunaga H. Validity of diagnoses, procedures, and laboratory data in Japanese administrative data. J Epidemiol. 2017;27(10):476–82. https://doi.org/10.1016/j.je.2016.09.009.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Yamane Y, Aihara M, Ikezawa Z. Analysis of Stevens–Johnson syndrome and toxic epidermal necrolysis in Japan from 2000 to 2006. Allergol Int. 2007;56(4):419–25. https://doi.org/10.2332/allergolint.O-07-483.

    CAS  Article  PubMed  Google Scholar 

  36. 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;65(1):74–81. https://doi.org/10.1016/j.alit.2015.09.001.

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kojiro Morita.

Ethics declarations

Conflict of interest

Kojiro Morita, Hiroki Matsui, Nobuaki Michihata, Kiyohide Fushimi, and Hideo Yasunaga declare that they have no conflicts of interest.

Funding

This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (H29-Policy-Designated-009 and H29-ICT-General-004); the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141); and the Japan Agency for Medical Research and Development (AMED). The funding source had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Ethical approval

This study was approved by the Institutional Review Board of The University of Tokyo.

Informed consent

The requirement for informed patient consent was waived because of the anonymous nature of the data.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1108 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Morita, K., Matsui, H., Michihata, N. et al. Association of Early Systemic Corticosteroid Therapy with Mortality in Patients with Stevens–Johnson Syndrome or Toxic Epidermal Necrolysis: A Retrospective Cohort Study Using a Nationwide Claims Database. Am J Clin Dermatol 20, 579–592 (2019). https://doi.org/10.1007/s40257-019-00443-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40257-019-00443-9