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This study examines the use of multiple biomarkers for the prediction and diagnosis of severe adverse drug reactions (ADRs) before the onset of clinical symptoms. The results suggest that a combination of phenotypic-specific biomarkers and disease progression markers can effectively identify patients at high risk for developing severe ADRs.
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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 Day7 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), prediction of the severity and diagnosis of disease at the initial presentation before appearance of typical clinical symptomsis challenge in some cases.
Biomarkers as important pathogenetic factors forSJS/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 ADRsControls Diagnosis of SJS, TEN and DIHS/DRESS was made based on their criteria. gFDEwas 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.
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 FasLand granulysinwere 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 eruptionat 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-10IL-5 IL-13 IFN g IL-7 SJS
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 sFasL 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.