Stevens-Johnson’s Syndrome / Toxic Epidermal … · 2018-02-16 · • Fluids • Electrolytes...
Transcript of Stevens-Johnson’s Syndrome / Toxic Epidermal … · 2018-02-16 · • Fluids • Electrolytes...
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Robert G. Micheletti, MD Assistant Professor of Dermatology and Medicine Director, Cutaneous Vasculitis Clinic, Penn Vasculitis Center Co-Director, Inpatient Consult Service University of Pennsylvania
Stevens-Johnson’s Syndrome / Toxic Epidermal Necrolysis: An update
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• Prodrome of fever, flu-like symptoms x 1-3 days
• Photophobia, conjunctival itching, dysphagia, skin tenderness
• Typically two or more mucous membranes
• Dusky atypical target lesions • Denuded skin / epidermal
detachment • SJS < 10% BSA • TEN > 30% BSA
Presentation
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Etiology and Pathogenesis
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Overall incidence of SJS/TEN 2-13 per million per year Risk factors include immune dysregulation:
HIV infection • 100-fold increase Autoimmune disease • 50-fold increase in SLE patients Active malignancy (particularly hematologic) • 30-to-60-fold increase
J Invest Dermatol. 2016;136(7):1387-97. Br J Dermatol. 2012 Mar;166(3):575-600.
Am J Clin Dermatol. 2012 Feb;13(1):49-54.
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Etiology and Pathogenesis
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Genetic factors • HLA-B*15:02 (carbamazepine; OR 79.84, Asian)* • HLA-A*31:01 (carbamazepine; all ethnic groups)* • HLA-B*58:01 (allopurinol) *Pre-screening of HLA type recommended prior to starting carbamazepine Polymorphisms in Cyt P450 and other factors associated with decreased medication clearance N Engl J Med. 2011;364(12):1126.
JAMA Dermatol. 2013;149(9):1025. J Dermatol Sci. 2014 Feb;73(2):101-9.
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Etiology and Pathogenesis
Drug-specific CD8 T-cells and natural killer (NK) cells are the major inducers of keratinocyte apoptosis Drugs stimulate the immune system by binding to MHC-I and T-cell receptors, resulting in clonal expansion of cytotoxic T-cells These cells kill keratinocytes directly and indirectly via release of cytotoxic mediators: • Soluble Fas ligand • Perforin / granzyme • Tumor necrosis factor • Granulysin
J Allergy Clin Immunol. 2011 Dec;128(6):1266-1276.
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Etiology and Pathogenesis
Granulysin • Produced and secreted by CD8 and NK cells • Highly expressed in SJS/TEN • Levels in blister fluid correlate with disease severity • Reproducible cytotoxic effect on keratinocytes • Thought responsible for apoptosis in SJS/TEN
*Being studied as a diagnostic marker and treatment target for SJS/TEN
Ann Intern Med. 2009;151(7):514. J Allergy Clin Immunol. 2008;122(5):992.
Curr Opin Allergy Clin Immunol. 2013 Aug;13(4):330-6. Curr Opin Allergy Clin Immunol. 2015 Aug;15(4):294-9.
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Etiology and Pathogenesis
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Medications are the most common cause of SJS/TEN • Typically within 1-3 weeks (avg = 14 days) • Unlikely after first 8 weeks of treatment
• Allopurinol* • Anticonvulsants • Sulfa antibiotics • Nevirapine • Oxicam NSAIDs
*Most common in EuroSCAR (17.4%)
J Am Acad Dermatol. 2008;58(1):25.
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Etiology and Pathogenesis US Derm Hospitalist Study (377 adult patients) • Most common cause of SJS/TEN, in 89.7%, was medication
reaction, including common culprit drugs:
Class of medications N=338
Antibiotics Trimethoprim/sulfamethoxazole β-lactam antibiotics Fluoroquinolones
165 (48.8%) 89 (26.3%) 42 (12.4%) 12 (3.6%)
Antiepileptic/Mood stabilizers Lamotrigine Phenytoin Carbamazepine
83 (23.7%) 32 (9.5%) 30 (8.9%) 7 (2.1%)
Allopurinol 29 (8.6%)
NSAIDs 18 (5.3%)
v
v
v
v
Micheletti et al, Society of Dermatology Hospitalists (submitted)
v
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Etiology and Pathogenesis
Derm Hospitalist Study: • All patients with lamotrigine-induced
SJS/TEN (n = 29) survived to discharge
• Exposure to phenytoin increased the risk of death (RR 3.82 (0.99-14.69))
• High mortality among those receiving pip/tazo (Zosyn) (73%)drug or underlying disease state?
For the most part, the specific drug trigger does not contribute significantly to mortality risk in SJS/TEN
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Etiology and Pathogenesis Mycoplasma • SJS trigger common in children • Significant mucosal but minimal skin
involvement • Tend to have better outcomes
• Now recognized as a distinct entity,
termed Mycoplasma-induced rash and mucositis (MIRM)
Derm Hospitalist Study: 2% of cases attributed to Mycoplasma; mortality among infectious cases overall 8% J Am Acad Dermatol. 2015 Feb;72(2):239-45.
J Eur Acad Dermatol Venereol. 2015 Mar;29(3):595-8.
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Rapid Diagnosis—a medical emergency
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When SJS/TEN is clinically obvious, institute therapy even if histologic confirmation is pending
• However, I do always perform a biopsy for completeness
• In one study, 1/3 of those biopsied received an alternate diagnosis based on histology
Burns. 2016 Feb 1. [Epub ahead of print].
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Transferred from an OSH, where he was diagnosed with SJS and treated in a burn unit… Ultimate diagnosis = severe cutaneous lupus
SJS Mimickers
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Transferred from an OSH to our ICU for treatment of SJS/TEN; received IVIG… Ultimate diagnosis = epidermolysis bullosa acquisita vs anti-epiligrin cicatricial pemphigoid
SJS Mimickers
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Patient with SLE on chronic immunosuppression Acute skin tenderness and widespread denuded skin concerning for SJS/TEN… Diagnosed with Staph scalded skin syndrome
SJS Mimickers
SSSS clinical pic
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SJS Mimickers
Patient with acute leukemia 2-3 weeks s/p stem cell transplant Developed acute dusky erythema, erosions, mucositis, conjunctivitis SJS/TEN vs grade IV acute GVHD…
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SJS Mimickers
Paraneoplastic pemphigus
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Rapid Diagnosis—a medical emergency
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• When the diagnosis is in doubt, biopsy may be required to guide management
• Histologic appearance of SJS: • Keratinocyte necrosis ranging from partial to full
thickness (established lesions) • Scant perivascular lymphohistiocytic inflammation
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• In our hospital, preliminary results of standard biopsy are available by the end of the following business day
• Alternative options: • Frozen section biopsy • Tzanck smear • “Jelly roll”
*Frozen section biopsy: Results typically available within 20-30 minutes Take the time to discuss with pathology and determine the mechanism for this in your hospital
Rapid Diagnosis
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Rapid Diagnosis
“Jelly roll” The blister roof can be submitted for frozen section
Reveals full-thickness epidermal necrosis
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Data-Driven Management
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Published overall mortality rate for SJS/TEN is 20-25% RegiSCAR cohort 6-week mortality: • SJS = 12% • SJS/TEN = 29% • TEN = 46%
Ther Adv Drug Saf. 2011;2(3):87. J Invest Dermatol. 2013 May;133(5):1197-204.
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Data-Driven Management
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How do we give our patients the best chance for survival? What management is supported by the available evidence?
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Data-Driven Management
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Stop the culprit drug
• Earlier withdrawal = better prognosis • OR of death = 0.69 for each day sooner • OR of death = 4.9 for drugs with long half lives
Identification of the causative agent is a non-trivial exercise • Causality assessment tools (e.g., ALDEN) may help but have
problems with reliability and agreement • No substitute for systematic approach by an expert (dermatologist)
Arch Dermatol. 2000;136(3):323. Clin Pharmacol Ther. 2017;101:S5-S99.
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Data-Driven Management
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Transfer the patient to an ICU or burn unit • In one study, overall mortality = 32% • Mortality of those transferred after > 1 week = 51%
*Patients with “mild” SJS or SCORTEN of 0 or 1 should still be cared for in an ICU • “Mild” SJS is a designation best made in retrospect;
patients may progress rapidly from mild presentations • Published guidelines suggest initial management of
SJS/TEN patients in specialized centers due to risk of rapid progression regardless of initial % BSA involved
Burns. 2016;42(4):836-43. J Burn Care Rehabil. 2002;23(2):87.
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Data-Driven Management
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• Fluids • Electrolytes • Temperature • Nutrition • Pain control • Airway maintenance
• Wound care • Infection surveillance • Ophthalmology • Gynecology • Urology • Hematology
The level of care is a surrogate for supportive care:
Medicine (Baltimore). 2010 Jan;89(1):28-36. J Am Acad Dermatol. 2013 Aug;69(2):187.e1-187.e16.
• Role of dermatology in diagnosis, identification of culprit drug • Role of dermatology as team “quarterback”
• Critical role in patient advocacy
Cleaning, lubrication, steroid drops Amniotic membranes, scleral spacers
2/3-3/4 Parkland formula Enteral, not parenteral Bacteremia in 27%:
Staph, Pseudomonas, Enterobacteriaceae Topical steroids, vaginal dilator, Vaseline gauze
Vaseline, non-stick gauze Clean / sterile technique
Close observation; may require prolonged intubation May develop profound neutropenia Urethritis, urinary retention
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Data-Driven Management
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Despite this, there is wide variability in supportive and systemic care: • Survey of 102 burn centers showed variability in
consultation of other services: • Ophthalmology (66%) • Dermatology (47%) • Gynecology (13%)
Burns. 2016 Jun;42(4):830-5.
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Data-Driven Management
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ICU versus Burn Center: • Burn centers are highly skilled in wound care and fluid
management, but do they have a dermatologist? • Burn center may be less familiar with management of complex
medical comorbidities • Patients who are post-transplant, have autoimmune disease, etc.
require specialized knowledge and care • Dermatology hospitalists may be best positioned to provide the
differential diagnosis, wound care, and advocacy patients need • Both are better than non-specialized ward, but supportive care
should be more homogeneous and studied prospectively
J Am Acad Dermatol. 2014 Jul;71(1):195-6.
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Besides supportive care, published literature has not consistently shown benefit from the use of any particular systemic therapy for SJS/TEN Case series and retrospective cohorts are limited by confounding factors, low numbers, and inherent biases that make drawing conclusions from existing data difficult
Latest Evidence for Pharmacotherapies
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Latest Evidence for Pharmacotherapies
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Systemic Corticosteroids: • Early observational studies indicated a higher
complication and mortality rate • EuroSCAR cohort suggested possible benefit to early
steroids, though not statistically significant • RegiSCAR cohort and systematic review: no mortality
advantage over supportive care alone
J Am Coll Surg. 1995;180(3):273 Ther Adv Drug Saf. 2011;2(3):87.
J Am Acad Dermatol. 2008;58(1):33. J Invest Dermatol. 2013 May;133(5):1197-204.
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Latest Evidence for Pharmacotherapies
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Systemic Corticosteroids: • More recently, a meta-analysis of 96 studies in JAMA
Dermatology, suggested there is a survival benefit
• While these results had limitations and were only marginally statistically significant, corticosteroids were felt to be promising
• On balance, despite concern for increased infection, early use of systemic steroids may be beneficial
JAMA Dermatol. 2017;153(6):514-22.
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Latest Evidence for Pharmacotherapies
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Intravenous Immunoglobulin:
• Data are limited and conflicting
• Thought to inhibit Fas—FasL binding, but this is no longer considered the primary mediator of SJS
Drugs. 2005;65(15):2085. Science. 1998;282(5388):490.
Arch Dermatol. 2003;139(1):26. Arch Dermatol. 2003;139(1):39.
Br J Dermatol. 2012 Aug;167(2):424-32.
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Latest Evidence for Pharmacotherapies
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Intravenous Immunoglobulin:
• Case series and a systematic review suggested “high-dose,” early IVIG (>2g/kg total) improves survival
• However, a number of reviews, including the recent meta analysis from 2017, have shown no mortality benefit
Drugs. 2005;65(15):2085. Science. 1998;282(5388):490.
Arch Dermatol. 2003;139(1):26. Arch Dermatol. 2003;139(1):39.
Br J Dermatol. 2012 Aug;167(2):424-32.
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Latest Evidence for Pharmacotherapies
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Intravenous Immunoglobulin:
• For these reasons, IVIG has fallen out of favor in Europe
• However, it continues to be an agent of choice for SJS/TEN among US dermatology hospitalists
Br J Dermatol. 2015 Nov;173(5):1250-4.
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Latest Evidence for Pharmacotherapies
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A survey of 131 US providers (academic dermatologists and burn centers) reported that: • Majority do not use systemic steroids • More likely to use IVIG if more severe disease majority
use IVIG for SJS/TEN overlap and TEN • Those who see SJS/TEN more frequently are more likely to
use IVIG regardless of severity
J Am Acad Dermatol. 2016 Feb;74(2):379-80.
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US Derm Hospitalist Study (377 adult patients)
In our cohort managed by inpatient dermatologists, IVIG was used extensively, alone or in combination (55.6% of patients) Patients receiving IVIG had more severe disease at presentation: • Higher median BSA involvement (30% vs 12%, p-value<0.01) • Higher rate of TEN (28.0% vs 18.7%, p-value=0.01) • Higher rates of severe ocular, oral, and genitourinary involvement
(all p-values <0.05) compared to other treatment groups
Micheletti et al, Society of Dermatology Hospitalists (submitted)
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Latest Evidence for Pharmacotherapies
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Intravenous Immunoglobulin: • In summary, no high quality evidence supports the use of IVIG
in SJS/TEN
• However, those who receive it appear to be sicker to start with, and the effects of this and other confounders may not be completely accounted for by SCORTEN-predicted mortality
Early in the disease course, a dose of 1g/kg/day x 3-4 days IVIG can be considered
• Potential side effects include clot / hyperviscosity • Side effect profile more favorable than high-dose steroids
Br J Dermatol. 2015 Nov;173(5):1250-4.
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Latest Evidence for Pharmacotherapies
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Cyclosporine:
• Anti-apoptotic, inhibits T-cells, including CD8 T-cells
• Dose 3 to 5 mg/kg/day, tapered over one month
• Supported mostly by small, retrospective, and uncontrolled case series
J Trauma. 2000;48(3):473. Cutis. 2011 Jan;87(1):24-9.
J Am Acad Dermatol 2012;67(4):630-5.
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Latest Evidence for Pharmacotherapies
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Cyclosporine: • Retrospective review of 64 patients • Outcome of 15 who received cyclosporine (SMR = 0.43)
better than 50 who received IVIG (SMR = 1.43) • IVIG dose and timing varied widely
• Retrospective review of 44 patients • Among 24 who received cyclosporine, SMR = 0.42
• Open, Phase II trial of 29 patients:
• SCORTEN predicted mortality 2.75; actual = 0
Br J Dermatol. 2010;163(4):847. J Am Acad Dermatol. 2014;71(5):941.
J Am Acad Dermatol. 2017;76(1):106-113
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Latest Evidence for Pharmacotherapies
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Cyclosporine:
• More recently, two 2017 studies suggested a mortality benefit of cyclosporine via meta-analysis and retrospective case series (49 patients)
• Increasing favor in Europe, but the actual number of treated patients remains small, and the drug has important side effects (renal, immunosuppression)
JAMA Dermatol. 2017;153(6):514-22. J Invest Dermatol. 2017 Oct;137(10):2092-100.
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Cyclosporine: • Letter-to-the-editor:
• Existing studies either exclude patients with renal insufficiency and other known SJS/TEN mortality risk factors altogether or do not report them
• In our cohort, renal failure was the greatest mortality RF
• Recent retrospective cohort study of 174 patients: • No significant benefit from cyclosporine in 95 patients
(versus 79 supportive care only) • Acute renal failure more common in treatment group
J Invest Dermatol. 2018 Jan 21 [Epub ahead of print]
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Cyclosporine: • In summary, cyclosporine is certainly deserving of further study,
but there are reasons to temper enthusiasm
• Early use of cyclosporine in young, otherwise healthy patients at a dose of 3-5mg/kg/day is a reasonable treatment option, but we do not have enough data to recommend this in sicker patients
JAMA Dermatol. 2017;153(6):514-22.
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Tumor Necrosis Factor (TNF) inhibitors: Thalidomide: • Only double-blind, randomized, placebo-controlled TEN study • Trial stopped early due to excess mortality (10/12 died, vs 3/10
in placebo)
Suggested reason for caution with respect to TNF inhibitors for SJS/TEN
Lancet. 1998;352(9140):1586.
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Tumor Necrosis Factor (TNF) inhibitors:
Etanercept: • Case series in 8/2014 JAAD • One 50mg injection • 10 patients with good outcomes;
no controls
Infliximab: • One 5mg/kg infusion • Case reports only
Pediatr Dermatol. 2014;31(4):532. J Am Acad Dermatol. 2014;71(2):278.
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Tumor Necrosis Factor (TNF) inhibitors: 96-patient randomized trial of etanercept versus corticosteroids • SMR = 0.47 among those receiving
etanercept (0.80 with corticosteroids) • Decreased time to skin healing and
lower rates of complications compared to corticosteroid group
J Clin Invest. 2018 Feb 5. [Epub ahead of print]
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Tumor Necrosis Factor (TNF) inhibitors: • Recent experience with etanercept is promising
• 25mg or 50mg etanercept twice weekly until skin lesions
healed
J Clin Invest. 2018 Feb 5. [Epub ahead of print]
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US Derm Hospitalist Study (377 adult patients)
• Overall and subgroup mortality less than predicted by SCORTEN • Predicted mortality for the overall cohort was 21.1%, vs 14.7% actual • Adjusting for SCORTEN, mortality was lower in the steroid + IVIG group
compared to IVIG or steroids alone and to supportive care only • *Bias toward using IVIG to treat patients with more severe SJS/TEN • *Only 5 patients treated with cyclosporine or etanercept
Overall N=368
IVIG only N=92
Steroid only N=116
IVIG + Steroid N=54
Supportive care N=117
In-hospital mortality SCORTEN predicted mortality, N (%) 77.7 (21.1) 21.6 (23.5) 20.8 (17.8) 11.6 (21.2) 22.7 (19.4)
Observed mortality 54 (14.7) 17 (18.5) 15 (12.9) 6 (10.7) 16 (13.7) SMR
(95%CI) 0.70
(0.58, 0.79) 0.79
(0.55, 0.92) 0.72
(0.48, 0.89) 0.52
(0.21, 0.79) 0.70
(0.47, 0.87)
Micheletti et al, Society of Dermatology Hospitalists (submitted)
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US Derm Hospitalist Study (377 adult patients) One of the largest existing SJS/TEN cohorts (largest in N America)
Overall survival rate better than reported in the literature and better than predicted by SCORTEN: • Published mortality rate 20-25% in our cohort, 14.7% • Large systematic review reported SMR 0.82-0.92 in our
cohort, the SMR was 0.70 (0.58, 0.79)
Ther Adv Drug Saf. 2011;2(3):87. Micheletti et al, Society of Dermatology Hospitalists (submitted).
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• Unclear if improved survival reflects excellent supportive care in tertiary centers, the presence of a consulting dermatologist, or inadequacy of SCORTEN as a predictive tool
• The optimal pharmacologic regimen remains uncertain • Some small published series support steroids + IVIG • Cyclosporine, etanercept, corticosteroids all reasonable • Need better ways to account and adjust for prescriber practices,
particularly with respect to IVIG severity bias
• Additional analysis of the cohort is ongoing
J Burn Care Res. 2012 Nov;33(6):e295-308. Indian J Dermatol Venereol Leprol. 2013;79(4):506.
Micheletti et al, Society of Dermatology Hospitalists (submitted).
US Derm Hospitalist Study (377 adult patients)
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At our institution, we favor: • Admission of all SJS/TEN patients to the MICU • At least 1:1 nursing care • Daily dermatology and universal ophthalmology and
gynecology consultation • Early high-dose IVIG (1g/kg/day) x 3-4 days with a goal to
try to stop progression (actively re-evaluating) • Given as soon as the diagnosis is made (regardless of
severity); early Rx may be the key with any treatment
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All retrospective studies and literature reviews are limited by heterogeneous populations, dosing, and confounding factors In general, a lack of consensus regarding the appropriate pharmacologic management of SJS/TEN persists, even among experienced providers
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Next Steps
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Research priorities: • Better understanding of the genetic and immunologic
basis of disease with prospective sample collection • Improved risk assessment so the reaction can be avoided • Investigation of novel treatments to inhibit granulysin
Br J Dermatol. 2015 Nov;173(5):1250-4.
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Research priorities: • Systematic evaluation of SJS/TEN sequelae and quality of life Survey study
• Establish “expert opinion” standard for supportive care Delphi effort
Br J Dermatol. 2016 Aug;175(2):422-4. Br J Dermatol. 2015 Nov;173(5):1250-4.
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Research priorities: • Revision of SCORTEN, which may overestimate mortality Improved prognostic model (SMR 0.99)
• Utilize existing networks to conduct a prospective SJS/TEN study and, ultimately, a randomized controlled trial
J Invest Dermatol. 2017;137(5S):S37
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Summary
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• SJS/TEN is a severe cutaneous adverse drug reactions with published mortality of 20-25%
• Dermatologists play a critical role in diagnosing this disease, differentiating mimickers, identifying and stopping culprit drugs, and coordinating treatment efforts
• Much progress still to make with respect to pathogenesis, prevention, and management dermatologists can and should be at the forefront of these efforts
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The Dermatology Foundation
has supported & advanced my career.