SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Abstract

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

Keywords: Electronic health record; Granulysin; HLA; Networks; Pharmacogenomics; Pharmacovigilance; Stevens-Johnson; T cells; Toxic epidermal necrolysis.

Figure 1. Distribution of participants at SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Participants representing 14 countries from six medical subspecialties, SJS/TEN advocacy groups, the US government, and the SJS/TEN research community gathered in Orlando, Florida, on March 2, 2017, for the inaugural SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation meeting. Thirty pre- and post-doctoral trainees attended and presented original research at this meeting.

Figure 1. Distribution of participants at SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Participants representing 14 countries from six medical subspecialties, SJS/TEN advocacy groups, the US government, and the SJS/TEN research community gathered in Orlando, Florida, on March 2, 2017, for the inaugural SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation meeting. Thirty pre- and post-doctoral trainees attended and presented original research at this meeting.

Figure 2. Pharmacogenomic testing to prevent SJS/TEN in Thailand and Singapore

A. Thai Vigibase and implementation. A. Following the incorporation of pharmacogenomics testing at Ramathibodi Hospital in Bangkok, Thailand, the number of pharmacogenomics tests performed rose from <500 in 2011 to >2,000 in 2015. Concurrently, with financial reimbursement supplied by the Thai universal health coverage scheme from 2014 onward, the number of reported cases of SJS/TEN collected through Thai-Vigibase fell demonstrating the efficacy of genetic testing to prevent SJS/TEN in this population. B. Pharmacovigilance in Singapore. Carbamazepine and allopurinol are two of the most common causes of SCAR in Singapore and the risk alleles associated with carbamazepine- and allopurinol-SCAR (HLA-B*15:02 and HLA-B*58:01, respectively) occur at high frequency in the Singapore population. In 2013, the primary regulatory body in Singapore, the Health Sciences Authority (HSA), in conjunction with the Ministry of Health recommended HLA-B*15:02 genotyping prior to initiation of carbamazepine as standard of care for new patients of Asian ancestry. Following this recommendation, only 1 case of carbamazepine-associated SJS/TEN in 4 years has been reported, a marked reduction in incidence from the pre-testing baseline of ~18 cases per year. For allopurinol, due to the low (2%) PPV of HLA-B*58:01 testing and lower efficacy or higher cost of alternative medications, genotyping was not recommended for routine standard of care for chronic gout patients initiating drug therapy, although testing facilities were identified so that physicians have the option to conduct genotyping for high-risk patients such as those with renal impairment.

Figure 2. Pharmacogenomic testing to prevent SJS/TEN in Thailand and Singapore

A. Thai Vigibase and implementation. A. Following the incorporation of pharmacogenomics testing at Ramathibodi Hospital in Bangkok, Thailand, the number of pharmacogenomics tests performed rose from <500 in 2011 to >2,000 in 2015. Concurrently, with financial reimbursement supplied by the Thai universal health coverage scheme from 2014 onward, the number of reported cases of SJS/TEN collected through Thai-Vigibase fell demonstrating the efficacy of genetic testing to prevent SJS/TEN in this population. B. Pharmacovigilance in Singapore. Carbamazepine and allopurinol are two of the most common causes of SCAR in Singapore and the risk alleles associated with carbamazepine- and allopurinol-SCAR (HLA-B*15:02 and HLA-B*58:01, respectively) occur at high frequency in the Singapore population. In 2013, the primary regulatory body in Singapore, the Health Sciences Authority (HSA), in conjunction with the Ministry of Health recommended HLA-B*15:02 genotyping prior to initiation of carbamazepine as standard of care for new patients of Asian ancestry. Following this recommendation, only 1 case of carbamazepine-associated SJS/TEN in 4 years has been reported, a marked reduction in incidence from the pre-testing baseline of ~18 cases per year. For allopurinol, due to the low (2%) PPV of HLA-B*58:01 testing and lower efficacy or higher cost of alternative medications, genotyping was not recommended for routine standard of care for chronic gout patients initiating drug therapy, although testing facilities were identified so that physicians have the option to conduct genotyping for high-risk patients such as those with renal impairment.

Figure 2. Pharmacogenomic testing to prevent SJS/TEN in Thailand and Singapore

A. Thai Vigibase and implementation. A. Following the incorporation of pharmacogenomics testing at Ramathibodi Hospital in Bangkok, Thailand, the number of pharmacogenomics tests performed rose from <500 in 2011 to >2,000 in 2015. Concurrently, with financial reimbursement supplied by the Thai universal health coverage scheme from 2014 onward, the number of reported cases of SJS/TEN collected through Thai-Vigibase fell demonstrating the efficacy of genetic testing to prevent SJS/TEN in this population. B. Pharmacovigilance in Singapore. Carbamazepine and allopurinol are two of the most common causes of SCAR in Singapore and the risk alleles associated with carbamazepine- and allopurinol-SCAR (HLA-B*15:02 and HLA-B*58:01, respectively) occur at high frequency in the Singapore population. In 2013, the primary regulatory body in Singapore, the Health Sciences Authority (HSA), in conjunction with the Ministry of Health recommended HLA-B*15:02 genotyping prior to initiation of carbamazepine as standard of care for new patients of Asian ancestry. Following this recommendation, only 1 case of carbamazepine-associated SJS/TEN in 4 years has been reported, a marked reduction in incidence from the pre-testing baseline of ~18 cases per year. For allopurinol, due to the low (2%) PPV of HLA-B*58:01 testing and lower efficacy or higher cost of alternative medications, genotyping was not recommended for routine standard of care for chronic gout patients initiating drug therapy, although testing facilities were identified so that physicians have the option to conduct genotyping for high-risk patients such as those with renal impairment.

Figure 3. Epidemiology of SJS/TEN in special populations

A. All cases of SJS/TEN seen at Groote Schuur Hospital in South Africa between 2005 and 2015 showing the proportion of offending drugs. The proportion attributable to nevirapine for that year is shown as a percentage. B. All cases of pregnant women with SJS/TEN seen at Groote Schuur Hospital between 2005 and 2015 showing the proportion of offending drugs.

Figure 4. Suggested multidisciplinary approach to management of acute and recovery phase SJS/TEN

Key points highlighted include the necessity to 1) recognize and stop the offending medication quickly, 2) provide care for SJS/TEN in a tertiary critical care center (most often a Burn Center), 3) consider all organ systems involved in SJS/TEN and consult relevant subspecialists early in the disease course, and 4) provide post-hospital and long-term follow-up for patients to management complications of SJS/TEN. AT: artificial tears; MF: moxifloxacin 0.5% ophthalmic solution; PA: prednisolone acetate 1% ophthalmic solution; FML: fluorometholone 0.1% ophthalmic ointment; AMT: amniotic membrane transplant.

Figure 4. Suggested multidisciplinary approach to management of acute and recovery phase SJS/TEN

Key points highlighted include the necessity to 1) recognize and stop the offending medication quickly, 2) provide care for SJS/TEN in a tertiary critical care center (most often a Burn Center), 3) consider all organ systems involved in SJS/TEN and consult relevant subspecialists early in the disease course, and 4) provide post-hospital and long-term follow-up for patients to management complications of SJS/TEN. AT: artificial tears; MF: moxifloxacin 0.5% ophthalmic solution; PA: prednisolone acetate 1% ophthalmic solution; FML: fluorometholone 0.1% ophthalmic ointment; AMT: amniotic membrane transplant.

Figure 5. Regulatory mechanisms in the United States

A. The FDA Adverse Event Reporting System (FAERS) is a spontaneous adverse event reporting database that is the primary tool used for the detection of safety signals by the FDA. Reports are generated on a voluntary basis by patients, consumers, and healthcare provider. Reports may be submitted to FAERS either directly by the consumer through the FDA MedWatch event reporting system or by drug manufacturers as determined by regulatory requirements. B. When a safety signal is identified there are a number of possible regulatory actions that may be issued by the FDA. Regulatory actions highlighted in blue represent options for drug label modifications to reflect the adverse event. Drug-associated SJS/TEN is most often reported in the Warnings and Precautions section but may also appear as a Boxed Warning or in the Post-Marketing Experience section of the drug label. Other potential regulatory actions are highlighted in green. These include 1) manufacturer issuance of a Dear Healthcare Professional (HCP) letter or a Drug Safety Communication (DSC), 2) use of post-marketing requirements (PMR) or post-marketing commitments (PMC) to further evaluate the event, 3) use of risk evaluation and mitigation strategies (REMS) to manage risk while enabling continued access to the drug, and 4) drug withdrawal. PV: pharmacovigilance.

Figure 6. Use of electronic health data to identify rare disease cases and for the discovery of genetic associations

A. For a phenotype of interest, an iterative algorithm incorporating multiple aspects of patient data is developed and validated to identify cases in the medical record. The predictive algorithm is deployed at the test site and replicated across additional sites. Identification of allelic variants associated with the phenotype of interest is achieved using genetic analysis of biobanked DNA linked to the research EHR. B. A predictive algorithm with high positive predictive value (PPV) relies on the incorporation of multiple forms of patient data including billing codes, medication history, clinic notes, and lab and test results. NLP: natural language processing.

Figure 7. Worldwide risk HLA allele and IM-ADR frequencies

Global epidemiology of SJS/TEN and frequency of known risk HLA alleles. Incidence of SJS/TEN and other SCAR are represented for populations around the globe. Known common HLA risk allele frequencies are shown and color-coded to match the associated drug. NSAIDs: nonsteroidal anti-inflammatory drugs; SSLR: serum-sickness like reaction; DRESS: drug reaction with eosinophilia and systemic symptoms; AGEP: acute generalized exanthematous pustulosis. Reproduced with permission from Peter et al.(205)

Figure 8. Proposed model of SJS/TEN immunopathogenesis

SJS/TEN affects the epidermis following interaction of pathogenic immune effector cells with drug-modified epitopes presented by HLA on the surface of keratinocytes. Cytotoxic CD8+ T cells, NK cells, and NKT cells that recognize HLA-drug epitopes produce cytolytic proteins such as granulysin and other mediators of inflammation. The result is widespread keratinocyte death, the formation of fluid-filled bullae containing immune cells, and, ultimately, epidermal necrosis and sloughing.

Figure 9. Strengths, Weaknesses, Opportunities, and Threats analysis for SJS/TEN clinical management and research

Participants at SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation contributed to a SWOT analysis to define unmet needs in SJS/TEN clinical care and research and to identify approaches to address these needs.

Figure 10. Integrated –omics approaches as part of personalized medicine in SJS/TEN

There exist multiple opportunities to apply personalized medicine approaches for the prevention and treatment of SJS/TEN. Part of these approaches will include integrated –omics platforms that link genetic, immunologic, ecologic, and other data within an individual patient to estimate risk of disease, facilitate precise and rapid diagnosis, inform prognosis and response to therapy, and predict which medications are safe for future use. Aggregation of these data may allow us to define the general principals of immunopathogenesis and genetics that may be applied more broadly to larger populations.

Figure 11. TO INCLUDE IN PATIENT PERSPECTIVES BOX (permission obtained from all participants to include photos)

Photo 1: Julie McCawley Photo 2: Katie Neimeyer with SJS/TEN survivor and PGA champion Gene Sauers Photo 3: Angela Anderson