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Table 1.  
Demographic Characteristics of Patients Admitted to the Hospital for Index Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis (N = 708)
Demographic Characteristics of Patients Admitted to the Hospital for Index Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis (N = 708)
Table 2.  
Factors Associated With Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis Recurrence
Factors Associated With Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis Recurrence
1.
Papay  J, Yuen  N, Powell  G, Mockenhaupt  M, Bogenrieder  T.  Spontaneous adverse event reports of Stevens-Johnson syndrome/toxic epidermal necrolysis: detecting associations with medications. Pharmacoepidemiol Drug Saf. 2012;21(3):289-296.
PubMedArticle
2.
Park-Wyllie  LY, Mamdani  MM, Juurlink  DN,  et al.  Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783-789.
PubMedArticle
3.
Mockenhaupt  M.  The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803-813.
PubMedArticle
4.
Finkelstein  Y, Soon  GS, Acuna  P,  et al.  Recurrence and outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Pediatrics. 2011;128(4):723-728.
PubMedArticle
5.
Phillips  EJ, Chung  WH, Mockenhaupt  M, Roujeau  JC, Mallal  SA.  Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol. 2011;127(3)(suppl):S60-S66.
PubMedArticle
6.
Chung  WH, Hung  SI, Hong  HS,  et al.  Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.
PubMedArticle
Research Letter
June 4, 2014

Recurrence and Mortality Following Severe Cutaneous Adverse Reactions

Author Affiliations
  • 1Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
  • 2Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
  • 3Sunnybrook Research Institute, Toronto, Ontario, Canada
JAMA. 2014;311(21):2231-2232. doi:10.1001/jama.2014.839

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions. Both primarily develop as idiosyncratic responses to drugs,1 resulting in extensive epidermal detachment. Recurrence has been reported in isolated cases, and the overall risk of recurrence is unknown. Given the rarity of SJS and TEN, valid inferences about recurrence rates require the study of large populations over an extended period. We examined the long-term risk of recurrence following a first SJS or TEN episode.

Methods

We conducted a 10-year population-based cohort study of all Ontario residents (>13 million) hospitalized for a first episode of SJS or TEN (International Statistical Classification of Diseases, 10th Revision [ICD-10] codes L511 or L512, respectively) between April 2002 and March 2011, excluding those with any such admission in the preceding 5 years. We linked comprehensive hospitalization data (from the Canadian Institute for Health Information Discharge Abstract Database), demographic and vital statistics (from the Registered Persons Database), and physician claims (from the Ontario Health Insurance Plan) in an anonymous fashion, as done previously.2

Patients were followed up from admission until March 31, 2012, or death. We explored SJS and TEN recurrence rates and short-term mortality using the Kaplan-Meier method, and compared patients with and without recurrent episodes using the t test, Mann-Whitney test, or χ2 test, as appropriate. We used Cox proportional hazards regression to explore factors associated with recurrence.

This study was approved by the research ethics board of Sunnybrook Health Sciences Centre and the requirement for consent from patients was waived. All analyses used SAS version 9.3 (SAS Institute) and a 2-tailed type I error of .05 as the threshold for statistical significance.

Results

We identified 708 individuals hospitalized for a first episode of SJS (n = 567; 80%) or TEN (n = 141; 20%), including 127 (17.9%) children younger than 18 years (Table 1). Overall, 187 patients (26%) were admitted to critical care or burn units and 127 (17.9%) died in the hospital (n = 84) or within 60 days of hospital discharge (n = 43), representing a short-term mortality rate of 23.4% for patients with TEN and 9.0% for SJS. We followed up the remaining 581 patients for a median of 1283 days (interquartile range [IQR], 429-2377 days), with a cumulative follow-up of 2621 person-years.

Forty-two patients (7.2%; 95% CI, 5.1%-9.4%) were hospitalized for a subsequent episode of SJS or TEN, which is equivalent to an incidence rate of 16 recurrent SJS or TEN episodes per 1000 person-years. Eight patients (1.4%; 95% CI, 0.4%-2.4%) experienced multiple recurrences. The median time to first recurrence was 315 days (IQR, 216-411 days). Factors associated with recurrence included male sex, rurality, and delivery of care at an academic hospital during the index admission (Table 2). Patients who developed recurrent SJS or TEN were significantly younger at the index episode compared with those who did not (P = .03; Table 1). Critical care admission rates (26%; 95% CI, 23.2%-29.7%) were similar at the index admission and subsequent episodes.

Discussion

In light of the reported incidence of SJS and TEN in the general population (1.0-7.2 cases/1 million individuals/year),3,4 the observed recurrence risk in our study (>7%) is several thousand-fold higher than would be expected if subsequent episodes were probabilistically independent of the first SJS or TEN episode. We speculate that this increased risk reflects individual susceptibility. Genetic predisposition has been identified for several medications in association with specific genotypes,5 such as carbamazepine-induced SJS in Chinese patients carrying HLA-B*1502 alleles.6 Additionally, SJS and TEN recurrence has been reported after exposure to structurally dissimilar drugs, such as carbamazepine and zonisamide.4

The main limitation of our study is the lack of direct access to patient records, and medication exposures in particular. In addition, there is no unique ICD-10 code for SJS-TEN overlap syndrome. Regardless, these findings are relevant to physicians who care for patients with a history of SJS or TEN. Because most such episodes are drug-induced, the high risk of recurrence should be recognized, and the benefits of drug therapy weighed carefully against the potential risks. This is particularly true for drugs commonly associated with the development of these frequently fatal conditions.

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Article Information
Section Editor: Jody W. Zylke, MD, Senior Editor.

Corresponding Author: Yaron Finkelstein, MD, ABCP(Dip), Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (yaron.finkelstein@sickkids.ca).

Author Contributions: Drs Finkelstein and Juurlink had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Finkelstein, Hutson, Juurlink.

Acquisition, analysis, or interpretation of data: Finkelstein, Macdonald, Li, Hutson.

Drafting of the manuscript: Finkelstein, Macdonald, Hutson, Juurlink.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Macdonald, Li.

Administrative, technical, or material support: Finkelstein, Hutson, Juurlink.

Study supervision: Finkelstein, Juurlink.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported by an emerging team grant from the Canadian Institutes of Health Research, Canadian Drug Safety and Effectiveness Research Network, and the Institute for Clinical Evaluative Sciences, a nonprofit research institute sponsored by the Ontario Ministry of Health and Long-Term Care.

Role of the Sponsor: The Canadian Institutes of Health Research, Canadian Drug Safety and Effectiveness Research Network, Institute for Clinical Evaluative Sciences, and the Ontario Ministry of Health and Long-Term Care 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 decision to submit the manuscript for publication.

Disclaimer: The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.

Additional Contributions: We thank Brogan Inc for use of their Drug Product and Therapeutic Class Database. We are deeply indebted to Teresa To, PhD, and Muhammad M. Mamdani, PharmD, MA, MPH (both with the Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada), for their advice and guidance. Drs To and Mamdani did not receive compensation for their roles.

References
1.
Papay  J, Yuen  N, Powell  G, Mockenhaupt  M, Bogenrieder  T.  Spontaneous adverse event reports of Stevens-Johnson syndrome/toxic epidermal necrolysis: detecting associations with medications. Pharmacoepidemiol Drug Saf. 2012;21(3):289-296.
PubMedArticle
2.
Park-Wyllie  LY, Mamdani  MM, Juurlink  DN,  et al.  Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA. 2011;305(8):783-789.
PubMedArticle
3.
Mockenhaupt  M.  The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis. Expert Rev Clin Immunol. 2011;7(6):803-813.
PubMedArticle
4.
Finkelstein  Y, Soon  GS, Acuna  P,  et al.  Recurrence and outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Pediatrics. 2011;128(4):723-728.
PubMedArticle
5.
Phillips  EJ, Chung  WH, Mockenhaupt  M, Roujeau  JC, Mallal  SA.  Drug hypersensitivity: pharmacogenetics and clinical syndromes. J Allergy Clin Immunol. 2011;127(3)(suppl):S60-S66.
PubMedArticle
6.
Chung  WH, Hung  SI, Hong  HS,  et al.  Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486.
PubMedArticle
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