Transcript A combination of early biomarkers useful for the prediction of severe

A combination of early biomarkers
useful for the prediction of severe
adverse drug reactions
Yumi Aoyama and Tetsuo Shiohara
Dermatology, Kawasaki Hospital Kawasaki Medical
School, Okayama, Japan
Dermatology, Kyorin University School of Medicine,
Tokyo, Japan
Day4
Initial presentation
Day7
After steroid pulse therapy
初診時の写真 とその後の写真
In severe adverse drug reactions (ADRs),
prediction of the severity and diagnosis of
disease at the initial presentation before
appearance of typical clinical symptoms is
challenge in some cases.
Day10
Consolidation phase
Biomarkers as important pathogenetic
factors for SJS/TEN
1.Soluble Fas ligand involved in the pathomechanisms of
SJS/TEN. Viard R et al. Science. 1998 Abe R. J Dermatol Sci. 2008
2.Granulysin is a key mediator for disseminated
keratinocyte death in Stevens-Johnson syndrome and toxic
epidermal necrolysis. Chung WH et al. Nat Med 2008
• However, to date there has been no single biomarker
available for diagnostic or predictive testing of severe
ADRs in terms of sensitivity and specificity. Thus,
simultaneous measurements of several biomarkers are
needed for reliable, noninvasive laboratory tests for
identifying patients at higher risk of developing severe
ADRs.
Serum levels of cytokines/chemokines in patients at the initial presentation were examined.
patients
ADRs
Controls
Viral
Healthy
SJS
TEN
gFDE
MP
exanthem
Control
a
Total
19
11
33
9
6
22
26
Age, years 52.6 ± 5.1 48.6 ± 6.9 53.6 ± 3.4 56.2 ± 7.6 48.7 ± 7.4 26.2±3.2* 45.4±2.2
DiHS/DR
ESS
(mean±S.E.)
Diagnosis of SJS, TEN and DIHS/DRESS was made based on
their criteria.
gFDE was defined as >10 typical FDE lesions with wellcircumscribed, deep-red macules displaying a bilateral, often
symmetrical distribution and involving >10% of the body surface
area (BSA) distributed on at least 3 of 6 different anatomic sites.
Materials and methods
• Methods
Blood samples were obtained at or near the time of the initial
presentation to the hospital (Kyorin University School of
Medicine).
Serum FasL and granulysin were measured by ELISA kit.
Cytokines were measured using Human Cytokine/Chemokine
Magnetic Bead Panel (Merckmillipore Inc., Billerica, MA, USA)
in Kawasaki medical school.
• Statistical analysis
To compare the results of each group, non
parametrical analysis (Mann-Whitney test) was performed.
Cytokines increased in each drug
eruption at the initial presentation
TEN
FasL
gFDE
IL-2
IL-1a
IL-16
IL-17
IL-6
IL-8
IL-15
G-CSF
IP-10
TNFa
DiHS
IL-10
IL-5
IFN g
IL-7
SJS
IL-13
Cytokines not involved in each drug eruption at the initial presentation
TEN
IL-5 , IL-13
DiHS
IL-6
IL-8
IL-15
IL-17
G-CSF
gFDE
IL-10
SJS
Conlusion
Biomarkers available as diagnostic and staging tools
for SJS/TEN could be divided into two categories
Phenotype-specific biomarkers
sFas L and granulysin
predict and identify patients at high risk for the
development of SJS/TEN
Biomarkers for disease progression
IP-10, IL-4, IL-6 and IL-15
monitoring the severity of the disease and for predicting
the necessity of immunosuppressive agents.