Invited review articleRecent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis
Introduction
Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are delayed-type cutaneous immune reactions with the involvement of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells activation [1]. At the onset of the SJS and TEN, patients present a rapidly developing blistering exanthema of purpuric macules and target-like lesions accompanied by mucosal involvement and skin detachment [2], [3], [4]. SJS/TEN has been defined as the same disease spectrum with different degrees of severity and extent of skin detachment; they could be recognized as severe cutaneous adverse drug reactions (SCARs) or drug hypersensitivity reactions, if the immune reactions are elicited by drugs. The clinical classification for SJS is to present less than 10% of skin detachment, greater than 30% for TEN, and 10–30% for SJS and TEN overlapping (SJS–TEN) [2]. The clinical characteristics of SJS/TEN are different from other non-bullous cutaneous reactions, such as maculopapular eruption (MPE) and drug reaction with eosinophilia and systemic symptoms [DRESS, also known as drug induced hypersensitivity syndrome (DIHS) or hypersensitivity syndrome (HSS)]. Although having rare incidences, SJS/TEN are potentially fatal with 10–40% mortality and the survivors frequently suffered from permanent complications, such as the eye sequelae [5], [6], [7], [8], [9].
Several types of medications are associated with the inductions of SJS/TEN, including aromatic antiepileptic drugs (AED) [e.g. carbamazepine (CBZ), fosphenytoin, lamortrigine (LTG), oxcarbazepine, phenobarbital, phenytoin (PHT)], allopurinol, nevirapine, and sulfamethoxazole [10], [11], [12]. In particular, SJS/TEN are frequently associated the uses of aromatic AEDs, such as CBZ, PHT, and LTG [13]. In addition to drugs, some infectious pathogens, such as mycoplasma, are also known to be able to induce SJS/TEN [14], [15].
Currently, an optimal treatment standard for patients with SJS/TEN remains unavailable. Controversial results had been reported in the intravenous immunoglobulin (IVIG) therapy [16], [17], and corticosteroids [18], [19]. The study of EuroSCAR concluded that no sufficient evidence indicated the superior effectiveness of monotherapy over supportive care for SJS/TEN [20]. The efficacy of anti-tumor necrosis factor-alpha (TNF-α) agents needs to be further verified through the clinical trials [16]. Beyond the treatment grasp, if the culprit drug is recognizable, the immediate withdrawal of the suspected offending drug is critical and important to stop or attenuate the CTLs/NK cells-mediated immune reactions against the skin and other organs [21].
Recent advances in pharmacogenomic studies have provided evidences for genetic predispositions to SJS/TEN. In particular, the strong genetic association between human leukocyte antigens (HLAs) and specific drugs-induced SJS/TEN makes the in-advance screening tests prior to drug intake be practicable to prevent SJS/TEN [22]. In addition, our recent studies on the pathogenesis mechanism of SJS/TEN have revealed that the specific T cell receptors (TCR) recognized the drug presented by specific HLA alleles, leading to CTLs activation and expression of downstream cytotoxic signals [23]. Granulysin produced by CTLs or NK cells was identified to be the key mediator for the disseminated keratinocyte death in SJS/TEN [23]. In this article, we review the genetic susceptibility, immune mechanisms, cytotoxic signals and therapeutic strategies derived from the understanding of the pathogenic and cytological aspects.
Section snippets
Genetic susceptibility
HLA alleles being the main genetic determinants of SJS/TEN was first proposed by Roujeau et al., who reported the weak associations of HLA-A29, B12, and DR7 in sulfonamide-related TEN, and HLA-A2, B12 in oxicam-related TEN in Europeans [24]. Following the immunological hypothesis, the most striking evidences of genetic susceptibility to SJS/TEN were provided by our findings that HLA-B*15:02 is strongly associated with CBZ-induced SJS/TEN [22], and HLA-B*58:01 with allopurinol-induced SJS/TEN or
Interaction of HLAs, drug antigens and T cell receptors
How could small drug molecules induce the dramatic immune reactions, such as SJS/TEN? Multiple factors may be involved in the patho-mechanism of SJS/TEN. As the HLA molecules are the main immune receptors for presenting the foreign antigens, we proposed that in addition to genetic biomarkers, HLA alleles play a pathogenesis role in SJS/TEN. In particular, the highly polymorphic property of HLA molecules among individuals offers a diverse interaction towards different kinds of drug antigens. The
Cytotoxic signals and immune molecules in SJS/TEN
The central hypothesis to explain the severe mucocutaneous lesions of SJS/TEN is the CTLs/NK cells-mediated immune reactions. Till now, three major classes of cytotoxic proteins, including the Fas–FasL, perforin/granzyme B, and granulysin, are generally advocated for the extensive skin necrosis in SJS/TEN.
Therapeutic strategies derived from the patho-mechanism understanding
Currently, an ideal treatment for SJS/TEN is still unavailable. The frequent immunomodulating therapies for SJS/TEN include IVIG, corticosteroids, or cyclosporine. Unfortunately, there is no available in vitro cell culture or animal model for evaluating potential therapeutic agents for SJS/TEN. All the therapeutic agents used now for SJS/TEN lack evidences obtained from randomized case–control clinical trials. As SJS/TEN is rare, it is difficult to prospectively enroll a large sample size to
Summary
A summary of molecular pathogenesis of drug-induced SCARs is proposed in Fig. 3, which shows the upstream genomic predisposition of HLA, drug antigens interaction, cytotoxic T cell activation, and the downstream signaling of immune mediators leading the different phenotypes of clinical presentation. The recent advances in the aspects of genetic and immunology of SJS/TEN give us a better understanding of the immune mechanism, biomarkers for disease prevention as well as provide the therapeutic
Acknowledgments
This work was supported by grants from the National Science Council, Taiwan (NSC 98-2314-B-182A-027-MY3, 98-2320-B-010-002-MY3), and grants from Chang-Gung Memorial Hospital (BMRPG-290011, CMRPG-290051).
Dr. Wen-Hung Chung has served as a dermatologist at Chang Gung Memorial Hospital, Taiwan since 1999. In 2008, he obtained the Ph.D. degree from the Taiwan International Graduate Program of Academia Sinica and National Yang Ming University, Taiwan. Dr. Chung has devoted himself into the investigation of severe adverse drug reactions (SCARs) for over a decade and his devotion and findings have great impact in clinic. Dr. Chung and his team has identified genetic and bio-markers for SCARs. He
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Dr. Wen-Hung Chung has served as a dermatologist at Chang Gung Memorial Hospital, Taiwan since 1999. In 2008, he obtained the Ph.D. degree from the Taiwan International Graduate Program of Academia Sinica and National Yang Ming University, Taiwan. Dr. Chung has devoted himself into the investigation of severe adverse drug reactions (SCARs) for over a decade and his devotion and findings have great impact in clinic. Dr. Chung and his team has identified genetic and bio-markers for SCARs. He identified strong genetic association of HLA-B*1502 with carbamazepine-induced Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) in Han Chinese and HLA-B*5801 with allopurinol-SCARs. In addition, he also discovered granulysin as the major mediator for the extensive keratinocyte death in SJS or TEN. These important breakthroughs had been published on Nature and Nature Medicine in 2004 and 2008, respectively. Currently, these markers have been used in clinic before prescription of carbamazepine and allopurinol to prevent patients from the development of SCARs. Since these contributions, Dr. Chung had received awards of the 2006 Top 10 Rising Stars in Taiwan, 2009 the 47th Ten Outstanding Young Persons in Taiwan, and 2011 the International League of Dermatological Societies (ILDS) Young Dermatologist International Achievement Award. Dr. Chung continues his research as well as clinical works for patients with SCARs. In 2012, he establishes the first drug hypersensitivity clinical and research center in Taiwan which receives referral cases of SCARs from all over Taiwan.