1. 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

2. Initial presentation After steroid pulse therapy Consolidation phase
Day Day Day10
Initial presentation After steroid pulse therapy Consolidation phase
初診時の写真　とその後の写真
In severe adverse drug reactions (ADRs), the severity of disease at the initial presentation, at which stage the full-blown picture is not fully apparent, is only a guide to prognosis:
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.

3. Biomarkers as important pathogenetic factors for SJS/TEN
1.Soluble Fas ligand involved in the pathomechanisms of SJS/TEN. Viard R et al. Science 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.
Recent studies have suggested that soluble Fas ligand (sFasL) and granulysin levels in serum can serve as important pathogenetic factors for Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN) .
However, there has been no single biomarker available for diagnostic or predictive testing of severe ADR in terms of sensitivity and specificity.
There is the need for reliable, noninvasive laboratory tests for identifying patients at higher risk of developing severe ADRs.

4. Serum levels of cytokines/chemokines in patients at the initial presentation were examined.
ADRs Controls
SJS
TEN
DiHS/DRESS
gFDE MP
Viral exanthema
Healthy Control
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
(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 well-circumscribed, 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.
Sera of patients with fixed drug eruption, drug induced maculopapular rash, viral infection were used as disease control.

5. 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.
Blood samples were obtained at their initial presentation to the hospital of Kyorin university.
Serum cytokines were measured as shown in this slide.

6. TEN gFDE DiHS SJS FasL TNFa IL-2 IL-13
　　　　　　　　　　　　　　　　　　　　Cytokines increased in each drug eruption　at the initial presentation
TEN
FasL
IL-6
IL-8
IL-15
G-CSF
IP-10
gFDE
IL-1a
IL-16
IL-17
DiHS
TNFa
IL-2
IL-10　　　　　　IL-5
IL-13
These Cytokines increased in each drug eruption　at the initial presentation
IFN g
IL-7
SJS

7. 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
These cytokines were not involved in each drug eruption at the initial presentation
SJS

8. Conlusion Phenotype-specific biomarkers sFas L and granulysin
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
In conclusion, biomarkers available as diagnostic and staging tools for SJS/TEN could be divided into two categories: sFas L and granulysin represent phenotype-specific biomarkers that can predict and identify patients at high risk for the development of SJS/TEN, while IP-10, IL-4, IL-6 and IL-15 represent another type of biomarkers that can be used for monitoring the severity of the disease and for predicting the necessity of immunosuppressive agents. Thus, unnecessary treatment with potent immunosuppressive agents could be avoided by measuring the latter type
of biomarkers.
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.