The Journal of Allergy and Clinical Immunology: In Practice
Review and Feature ArticleSJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the severest in the spectrum of immunologically mediated adverse drug reactions (IM-ADRs) that are considered to be primarily T-cell–mediated. SJS/TEN is characterized by a painful blistering skin rash that is often associated with multiorgan involvement, commonly fever, hematologic abnormalities, and ophthalmologic and genitourinary involvement. Early dermatologic findings may include erythematous or dusky colored macules that evolve to become fluid-filled bullae and/or denuded skin. Involved nonblistered skin often sloughs with direct lateral pressure (Nikolsky sign) and demonstrates interface dermatitis with necrotic keratinocytes and epidermal separation on histopathologic examination (Table I). SJS and TEN are thought to be the same disease across a spectrum of severity defined by the percentage of skin detachment related to the body surface area (BSA) comprising SJS (<10%), SJS/TEN overlap (10%-30%), and TEN (>30%) (Table I). The mortality associated with TEN in the setting of aggressive supportive care at experienced centers is approximately 30%; however, in the elderly and immunocompromised populations this can exceed 50%. The short-term morbidity associated with SJS/TEN is well recognized and includes sepsis, respiratory complications, gastrointestinal and genital tract mucositis, and eye disease. However, long-term morbidity is also considerable and includes vision loss, urogynecological complications, chronic respiratory disease, depression and posttraumatic stress, disfigured painful skin, restricted therapeutic choices, and shortened life span. Over the last 10 to 15 years, there have been significant advances in our understanding of the immunogenomics of IM-ADRs.2 For SJS/TEN this has included several strong associations from Southeast Asia between HLA class I alleles and drug-associated SJS/TEN including HLA-B*15:02 and carbamazepine SJS/TEN and HLA-B*58:01 and allopurinol SJS/TEN. This has led not only to successful HLA-B*15:02 screening programs in Taiwan, Singapore, and other parts of Southeast Asia that have almost eliminated carbamazepine-associated SJS/TEN, but also furthered our understanding of the immunopathogenesis of SJS/TEN. Despite this progress there are still a large number of clinical and research gaps. A few highlights of these gaps include the lack of (1) an evidence-based approach to guide therapeutic interventions above aggressive supportive care in acute SJS/TEN, (2) predictive biomarkers for early diagnosis and prognosis, (3) genetic predictors for most drugs that cause SJS/TEN, and (4) an explanation for why only a small proportion (<10%) of those carrying an HLA risk allele will develop SJS/TEN following drug exposure.2
To explore gaps and unmet needs for further research into the epidemiology, pathogenesis, treatment, and prevention of SJS/TEN, the National Human Genome Research Institute, along with the Food and Drug Administration and 5 other National Institutes of Health institutes and centers (the National Center for Advancing Translational Sciences, the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis, Musculoskeletal and Skin Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases), brought together 30 international experts in severe cutaneous adverse reactions, pharmacogenomics, and related fields for a 2015 workshop titled “Research directions in genetic predispositions to SJS/TEN.”.3, 4 This 2-day workshop reviewed the current state of knowledge of surveillance, pathogenesis, and treatment of SJS/TEN, examined the role of genomics in the etiology, treatment, and eradication of preventable cases of SJS/TEN, and identified gaps, unmet needs, and priorities for future research to work toward the global elimination of genetically mediated SJS/TEN. A primary conclusion of this meeting was that although there have been great research strides in SJS/TEN with compelling examples of implementation of personalized medicine, there is continued need to broaden these discoveries for translation and implementation across diverse populations and causative drugs. Overarching and facilitative research goals were set and 3 high priority areas were identified and targeted: clinical care, pharmacovigilance and epidemiology, and basic research. An important outcome of the meeting was recognition of the need, because of the overall rarity and diverse epidemiology of SJS/TEN, to develop a large global collaborative network and a supportive funding infrastructure to further all aspects of SJS/TEN research.
An ongoing dialogue among an SJS/TEN working group comprising members from academia and government followed this meeting and has led to new initiatives that have included the establishment of an SJS/TEN phenotyping group that published a standardized case report form for SJS/TEN,5 a subgroup evaluating SJS/TEN causality assessment tools, and a national survey of dermatologists, burn surgeons, and ophthalmologists who care for patients with SJS/TEN that identified knowledge gaps, priorities, unmet needs, and unresolved controversies in SJS/TEN clinical care and research. More than 50% of survey respondents were interested in the opportunity for further engagement in all aspects of SJS/TEN research.6
The fundamental clinical, epidemiological, and basic research questions identified in the 2015 National Institutes of Health workshop served as a catalyst for further efforts toward organized collaboration. To engage a broad constituency of stakeholders in this effort, a meeting “Stevens-Johnson-syndrome/Toxic epidermal necrolysis 2017: Building Multidisciplinary Networks to Drive Science and Translation” was held on March 2, 2017. This meeting had representation across allergy-immunology, dermatology, ophthalmology, burns surgery, gynecology, clinical pharmacology, basic science (immunobiology, genetics), epidemiology, informatics, regulatory science, patients and their families, and government and included 142 participants from 6 continents (Figure 1). A major goal of this meeting was to bring together established and new investigators to create a durable network of SJS/TEN clinicians and scientists to discuss and prioritize achievable short- and long-term research objectives. This meeting was charged with presentation of the most current and cutting-edge research relevant to SJS/TEN, provision of mentorship for new investigators of disparate backgrounds to become future leaders in SJS/TEN, and, importantly, to provide a multidisciplinary and interactive forum where the most controversial areas of SJS/TEN clinical care and research could be discussed. The meeting highlighted key areas amenable to network building and clinical translation. Representatives from 3 National Institutes of Health institutes—the National Human Genome Research Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Arthritis, Musculoskeletal and Skin Diseases—provided updates on funding mechanisms relevant to SJS/TEN with a focus on newer R01/R21 funding related to serious IM-ADRs.7, 8
This article is a summary of the proceedings of the meeting that includes the new and evolving science, key controversies, outputs of the meeting, and proposed future directions.
Section snippets
Global Epidemiology and Pharmacogenomics Networks∗
Key Points:
- •
SJS/TEN is a life-threatening mainly drug-induced disease with considerable short- and long-term morbidity and mortality that poses a burden to health care systems and families disproportionate to its prevalence.
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The rarity of SJS/TEN has created
Special Populations and Considerations∗
Key Points:
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SJS/TEN survivors frequently suffer from psychological complications and decreased health-related quality of life. Prompt recognition and treatment is needed to address the psychological sequelae of SJS/TEN.
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Drugs that are commonly suspected to cause SJS/TEN in children are similar to causative drugs in adults
Clinical Management∗
Key Points:
- •
Cessation of the implicated drug and intensive supportive care with early multidisciplinary involvement is key to the management of SJS/TEN.
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Up to 77% of
Pharmacovigilance and the Electronic Health Record∗
Key Points:
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The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), a database of spontaneous adverse event reports, is the primary tool used by the FDA to detect safety signals of SJS/TEN in the postmarketing setting.
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The Singapore Health Sciences Authority (HSA) has evaluated 2 common (∼15%-20% carriage) HLA allele-drug pairs associated with SJS/TEN:
- ○
SJS/TEN Prevention, Prediction, and Pathogenesis: What's New and What's Next∗
Key Points:
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HLA-associated SCARs including SJS/TEN have provided models for T-cell–mediated ADRs and a roadmap for assessment and implementation of pharmacogenomic screening that can be applied in clinical use for the prevention of drug hypersensitivity. Despite strong HLA associations, PPVs
Discussion and Future Directions
SJS/TEN is a life-threatening disease that in adults is usually drug related and in children in particular, both SJS/TEN and its mimickers (Table I) can create unique diagnostic challenges in the absence of an apparent causative agent. The low incidence of SJS/TEN of 1 to 5 per 1,000,000 and high mortality rate have highlighted the need for research and clinical networks to drive research, translation, consensus guidelines, and evidence-based approaches. This 1-day meeting highlighted that
Acknowledgements
We thank freelance graphic designer Karen Adamson (Cape Town, South Africa) who helped with illustrations for Figures 7, 8, and 10.
Web resources and support services for patients with SJS/TEN: General SJS Foundation (http://www.sjsupport.org/sjsupport_group_facilitators.shtml); Stevens Johnson Syndrome Canada (http://www.sjscanada.org); Amalyste (France; http://www.amalyste.fr/); SJS Awareness UK (United Kingdom; https://www.sjsawareness.org.uk).
References (212)
- et al.
Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response
J Allergy Clin Immunol
(2015) - et al.
Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry
J Clin Epidemiol
(1996) - et al.
Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study
J Investig Dermatol
(2008) - 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) - et al.
Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis
J Investig Dermatol
(2013) - et al.
Psychometric properties of the Impact of Event Scale - Revised
Behav Res Ther
(2003) - et al.
Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life
J Investig Dermatol
(2011) - et al.
Pediatric Stevens-Johnson syndrome and toxic epidermal necrolysis in the United States
J Am Acad Dermatol
(2017) - et al.
Ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis in children
Am J Ophthalmol
(2016) - et al.
Genetic variations in HLA-B region and hypersensitivity reactions to abacavir
Lancet
(2002)
Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir
Lancet
Performance of the SCORTEN during the first five days of hospitalization to predict the prognosis of epidermal necrolysis
J Investig Dermatol
Toxic epidermal necrolysis in a mother and fetus
J Am Acad Dermatol
Assessment of “fresh” versus “macerated” as accurate markers of time since intrauterine fetal demise in low-income countries
Int J Gynaecol Obstetr
UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016
J Plast Reconstr Aesthet Surg
UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016 (print summary - Full guidelines available at https://doi.org/10.1016/j.bjps.2016.01.034)
J Plast Reconstruct Aesthet Surg
Treatment of toxic epidermal necrolysis in North America
J Am Acad Dermatol
Toxic epidermal necrolysis: five years of treatment experience from a burn unit
J Am Acad Dermatol
Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS): experience with high-dose intravenous immunoglobulins and topical conservative approach. A retrospective analysis
Burns
Methylprednisolone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis: clinical evaluation and analysis of biomarkers
J Am Acad Dermatol
SCORTEN: a severity-of-illness score for toxic epidermal necrolysis
J Investig Dermatol
Stevens-Johnson syndrome and toxic epidermal necrolysis standard reporting and evaluation guidelines: results of a National Institutes of Health Working Group
JAMA Dermatol
HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children
Clin Pharmacol Therapeut
Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions
Epilepsia
Phenotype standardization for immune-mediated drug-induced skin injury
Clin Pharmacol Therapeut
Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population
J Antimicrob Chemother
Toxic epidermal necrolysis (Lyell syndrome): incidence and drug etiology in France, 1981-1985
Arch Dermatol
Toxic epidermal necrolysis and Stevens-Johnson syndrome: an epidemiologic study from West Germany
Arch Dermatol
Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis
N Engl J Med
Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis
Aids
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
A marker for Stevens-Johnson syndrome…: ethnicity matters
Pharmacogenomics J
A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs
Pharmacogenet Genomics
ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson syndrome and toxic epidermal necrolysis: comparison with case-control analysis
Clin Pharmacol Therapeut
Pharmacogenomics of drug-induced hypersensitivity reactions: challenges, opportunities and clinical implementation
Asian Pac J Allergy Immunol
HLA-B allele and haplotype diversity among Thai patients identified by PCR-SSOP: evidence for high risk of drug-induced hypersensitivity
Front Genet
HLA-B (*) 58:01 for allopurinol-induced cutaneous adverse drug reactions: implication for clinical interpretation in Thailand
Front Pharmacol
Association between HLA-B*1502 and carbamazepine-induced severe cutaneous adverse drug reactions in a Thai population
Epilepsia
Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population
Pharmacogenet Genomics
The Japanese Postmarketing Adverse Event Relief System: a confluence of regulatory science, the legal system, and clinical pharmacology
Clin Pharmacol Therapeut
Japanese Research Committee on Severe Adverse Reaction (J-SCAR). Epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis throughout Japan: supported by the Japanese Research Committee on Severe Adverse Reactions (J-SCAR) and partially by Health and Labor Sciences research grants (Research on Intractable Diseases) from the Ministry of Health, Labor and Welfare of Japan and the Japanese Dermatological Association
Jpn J Dermatol
HLA-B*1511 is a risk factor for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients
Epilepsia
Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population
Hum Mol Genet
Epidemiology of severe drug hypersensitivity
Semin Cutan Med Surg
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This article represents a summary of a meeting, SJS/TEN 2017, that was held on March 2, 2017, preceding the American Academy of Dermatology meeting in Orlando, Fla.
Funding for this conference was made possible (in part) by the National Institutes of Health (NIH) (grant no. 1 R13AR71267-01), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and all cofunding support provided by the National Human Genome Research Institute, the National Center for Advancing Translational Sciences, the National Eye Institute, the National Institute of Allergy and Infectious Diseases, the US Food and Drug Administration, and the NIH/NCI Cancer Center (grant no. P30 CA008748). Funding was also provided by Teijin; Pharmigene, Inc; Eli Lilly Canada, Inc; Adaptive Biotechnologies; Bristol-Myers Squibb; Dunn Sheehan, LLP; Ocular Surface Center; HM Bio, LLC; Illumina; and Murdoch Global University, Australia, Dubai, Singapore.
Conflicts of interest: K. D. White has received research support from the National Institutes of Health (NIH). T. Beachkofsky is an Active Duty Officer in the United States Air Force. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Air Force, the Department of Defense, nor the US government. B. Carleton has received research support from the Canadian Institutes of Health Research, Canada Foundation for Innovation, Genome Canada Genome Columbia, and Provincial Health Services Authority and has received consultancy fees from AEVI Genomic Medicine. J. H. Holmes IV has stocks in Abbott Labs, Abbvie, and PermeaDerm, Inc. M. E. Lacouture has received support from Genentech and Roche.
S. Mallal has Equity in IIID Ltd that holds patents for HLA-B*57:01 screening for abacavir hypersensitivity. C. M. Mitchell has received personal fees from Symbiomix Therapeutics Inc. M. Mockenhaupt has received research support from Boehringer Ingelheim, Sanofi-Aventis, Tibotec-Janssen, Grünenthal, UCB-Pharma, and BIAL; has received personal fees from Pfizer and Merck; receives royalties from UpToDate; and has served as an expert witness in legal cases of Stevens-Johnson syndrome/toxic epidermal necrolysis in the United States (last July 2016). M. Pirmohamed has received research support from the UK Medical Research Council and the International Serious Adverse Event Consortium. E. Pope has received consultancy fees from Abvvie and ProQI; has received research support from Galderma; and has received consultancy fees and research support from Pierre Fabre Pharmaceuticals. J.-C. Roujeau has received personal fees from Ipsen Menarini, Pfizer, Novartis, Clinigen, Ab-Science, and UpToDate and has been a paid expert witness for US lawyers in several cases of SJS/TEN (more than 36 months ago). H. Sueki has received research support from the Ministry of Health, Labor and Welfare of Japan. K. B. Williams has received research support from the NIH. N. H. Shear has received research support from Lilly Canada and the NIH; has received speaker fees from Takeda; and is an unpaid board member of the Canadian Stevens-Johnson Foundation. E. J. Phillips has received research support from the National Health and Medical Research Council Australia, the NIH, and ACH2 Australia; receives royalties from UpToDate; has received consultancy fees from Biocryst, Aicuris, Xcovery, and Medicines for Malaria (MMV); and is codirector of the company holding the patent for HLA-B*57:01 testing for abacavir hypersensitivity reaction. The rest of the authors declare that they have no relevant conflicts of interest.