Severe cutaneous adverse drug reactions

Abstract

The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T-cell receptor (TCR): (i) the "hapten/prohapten" theory; (ii) the "p-i concept"; (iii) the "altered peptide repertoire"; and (iv) the "altered TCR repertoire". The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA-B*15:02 for carbamazepine-induced SJS/TEN and HLA-B*58:01 for allopurinol-induced SCAR), involvement of specific TCR, induction of T-cell-mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T-helper 1/2-associated cytokines) and cell death mechanism (e.g. miR-18a-5p-induced apoptosis; annexin A1 and formyl peptide receptor 1-induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin-induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved.

A Review of the Pathogenesis of Toxic Epidermal Necrolysis

“…As a result, self peptides that bind to the HLA-drug complex for display to TCR are altered from the self-peptides that bind to the original HLA. Thus different T cell are triggered 3,5,7,10 . In the altered TCR repertoire, the same thing happens as in the altered peptide repertoire, but this time the drug binds to a specific TCR, and changes the structure of the TCR.…”

MicroRNA and gene signature of severe cutaneous drug hypersensitivity reactions reveal the role of miR-483- 5p/miR-28-5p in inflammation by targeting Granulysin gene

“…The pathogenesis of SCAR is a compound and multifactorial. It is known that drug antigen interactions, genetic background, and environmental factors might be involved [2]. SCAR are among the most significant serious skin conditions amid cutaneous drug-provoked hypersensitivity adverse conditions [3].…”

Toxic epidermal necrolysis after dactinomycin and vincristine combination chemotherapy for nephroblastoma

“…The study of Hockett (2004) is very nonspecific regarding the types of malignancies connected with SJS and TEN, but this association may be related to the drugs used to treat specific malignancies or their side effects. In addition, there remain approximately 20% of SJS/TEN cases without an identified cause (Schwartz et al, 2013;Chung et al, 2016).A 2-year-old boy was admitted to the Department of Urological Surgery, Beijing Children's Hospital, Capital Medical University, Beijing, China, with an abdominal mass that ultrasound and computed tomography examination revealed as a left kidney nephroblastoma (size 15.8 cm×14.5 cm×12.4 cm) with pulmonary and osseous metastases, and the patient received combination chemotherapy with dactinomycin (Cosmegen; 15 μg/(kg·d) intravenously in the first 5 d) and vincristine (1.5 mg/(m 2 ·d) intravenously once per week). After one week, he developed multiple morbilliform rashes initially over limbs, then chest, with high fever, and his rash quickly progressed into a widespread confluent erythematous and necrosis eruption with blistering (Figs.…”

“…The majority of cases of SJS/TEN are the results of a hypersensitive reaction to a drug, and the drugs most commonly associated with the diseases are anticonvulsants, sulfa preparations, antibiotics, nonsteroidal anti-inflammatory drugs, allopurinol and antiretroviral drugs, etc. (Chung et al, 2016). In addition to drugs, other precipitating factors include the infection-, malignancy-, collagen-, and vascular-related factors.…”

“…The study of Hockett (2004) is very nonspecific regarding the types of malignancies connected with SJS and TEN, but this association may be related to the drugs used to treat specific malignancies or their side effects. In addition, there remain approximately 20% of SJS/TEN cases without an identified cause (Schwartz et al, 2013;Chung et al, 2016).…”