stevens-johnson’s syndrome / toxic epidermal necrolysis ... s020 - micheletti -...

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

• 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

Etiology and Pathogenesis

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.

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.

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.

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.

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.

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%)

Micheletti et al, Society of Dermatology Hospitalists (submitted)

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

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.

Rapid Diagnosis—a medical emergency

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].

Transferred from an OSH, where he was diagnosed with SJS and treated in a burn unit… Ultimate diagnosis = severe cutaneous lupus

SJS Mimickers

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

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

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…

SJS Mimickers

Paraneoplastic pemphigus

Rapid Diagnosis—a medical emergency

• 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

• 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

“Jelly roll” The blister roof can be submitted for frozen section

Reveals full-thickness epidermal necrosis

Data-Driven Management

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.

How do we give our patients the best chance for survival? What management is supported by the available evidence?

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.

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.

• 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

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.

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.

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

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.

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.

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.

• 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.

• 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.

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.

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

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.

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.

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

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.

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]

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.

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.

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.

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]

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]

• 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)

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).

• 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).

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

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

Next Steps

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.

Next Steps

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.

Next Steps

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

Summary

• 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

The Dermatology Foundation

has supported & advanced my career.

Thank you

Robert.Micheletti@uphs.upenn.edu University of Pennsylvania

stevens-johnson’s syndrome / toxic epidermal necrolysis ... s020 - micheletti -...

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