Drug-induced Maculopapular Exanthema Research Articles

A prospective observational study validating the CET score as a screening tool in suspected DRESS syndrome.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is an idiosyncratic severe cutaneous adverse reaction that may be potentially life-threatening. Recently, a simple scoring system for the early screening of DRESS patients was derived by combining hsCRP levels, the eosinophil count, and the total body surface area (CET score). The objectives of this study were validating the CET score,and calculating its lead time advantage and cost-benefits compared to RegiSCAR scoring. This is a prospective observational case-control study, where 110 consecutive patients diagnosed with drug-induced maculopapular exanthema (MPE) were recruited during the 18 months of the study period. Patients were classified as cases (DRESS) and controls (MPE) using RegiSCAR score cut-off 2 (possible DRESS). They were also simultaneously screened using the CET score, based on which patients were classified as positive or negative. They were subsequently followed up on Day 15 for a second comparison and assessment of lead time and at 3 and 6 weeks to evaluate clinical response. Seventy cases and 40 controls were recruited. At a cut-off of >2.12, the CET score had a sensitivity of 94.3%, a specificity of 60%, a positive predictive value (PPV) of 80.5%, and a negative predictive value (PPV) of 85.7%. The median delay in diagnosing DRESS using RegiSCAR was around 14.5 hours. There was a median cost benefit of 12.1 USD in favor of the CET score. The CET score had good diagnostic performance in screening DRESS patients with a lead time of 14.5 hours and fewer costs incurred.

HLA Risk Alleles in Aromatic Antiepileptic Drug-Induced Maculopapular Exanthema.

To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, p c = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.

072 Activation status of cutaneous and blood eosinophils in Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

DRESS is a drug-induced hypersensivity syndrom that can lead to severe organs failure. The role of cutaneous (c-Eo) and blood eosinophils (b-Eo) in tissue damage remains unknown. We aimed to analyze their activation status in DRESS. We collected retrospectively paraffin-embedded skin biopsies for patients from a French University hospital, who fulfilled criteria for drug-induced maculopapular exanthema (EMP) or DRESS. 1) in 38 patients (18 EMP and 20 DRESS), c-Eo and extracellular eosinophilic granules (ECP, MBP) were identified by immunohistochemical staining and quantified by an original semi-automatic method according to the color deconvolution and circularity parameters. 2) Fluorescence Activated Cell Sorting (FACS) was performed for activation markers of b-Eo in 4 DRESS and 4 healthy subjects. The number of c-Eo was significantly higher in DRESS patients (with anti-MBP staining, p=0,044). Analysis restricted to patients with Eo infiltrate in skin showed that granules were more frequent in the DRESS group according to the number of degranulation areas (p=0,027) and area of degranulation (p=0,02) suggesting that c-Eo from DRESS patients were activated. Analysis of activation markers of b-Eo by FACS showed lower expression of tissue-homing markers like CRTH2 (p=0,018) or activation markers like CD63 (p=0,029) and HLA-DR (p=0,029) in patients with DRESS suggesting a down-regulation of surface markers on b-Eo correlated with their activated status in the skin. Further study will be necessary to better understand the mechanisms of Eo recruitment in DRESS.

Expression of the Tim3-galectin-9 axis is altered in drug-induced maculopapular exanthema.

Drug-induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin-9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3-Gal9 axis on the development of MPE induced by drugs. Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT-qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3-Gal9 axis on monocyte-derived dendritic cell (moDC) maturation and T-cell proliferation were determined by flow cytometry. The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased. This study showed the involvement of the Tim3-Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.

Proliferation control of specific-effector T cells and T-Regulatory cells by Tim-3 and Galectin-9 in Drug-Induced Maculopapular Exanthema

Proliferation control of specific-effector T cells and T-Regulatory cells by Tim-3 and Galectin-9 in Drug-Induced Maculopapular Exanthema

Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS)

Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a serious acute drug reaction with fever, cutaneous eruption, lymphadenopathy, and several visceral dysfunctions. Eosinophilia is a common hematological abnormality in DIHS/DRESS suggesting that the Th2-type immune response is involved. Thymus and activation-regulated chemokine (TARC/CCL17) is a family of CC chemokines known to play an important role in Th2-mediated immune-inflammatory processes. We investigated the pathogenic role of TARC in patients with DIHS. Sera were obtained from 8 patients with DIHS, 7 patients with Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), and 14 patients with drug-induced maculopapular exanthema (MPE). Serum TARC levels were measured by ELISA. TARC levels were then compared with clinical symptoms and various hematological parameters. In addition, a biopsy was taken from the lesional skin of patients with DIHS and stained with anti-TARC Ab and anti-CD11c Ab. Serum TARC levels in patients with DIHS were significantly higher than those in patients with SJS/TEN and MPE during the acute phase. Serum TARC levels in DIHS patients correlated with skin eruptions, serum sIL-2R levels, eosinophil counts, and serum IL-5 levels. Immunohistochemical staining revealed that TARC was mainly expressed on CD11c+ dermal dendritic cells in patients with DIHS. Serum TARC levels may be associated with the initial presentation of DIHS as well as disease activity during the course. Thus, they could be useful as an indicator for early diagnosis and assessment of disease activity in DIHS. CD11c+ dendritic cells may be the main source of TARC in patients with DIHS.

Expression of α-defensin 1-3 in T cells from severe cutaneous drug-induced hypersensitivity reactions

Cytotoxic T cells seem to be the main effector cells in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). However, recent data support a role of the innate immune system in the etiopathology of drug-induced cutaneous reactions. In this study, we analyzed the expression of α-defensins 1-3 in mononuclear cells from patients with SJS/TEN, drug-induced maculopapular exanthema (MPE), and healthy donors. DEFA1A3 gene expression was analyzed by quantitative and end-point RT-PCR. Intracellular flow cytometry, immunofluorescence and immunohistochemistry were carried out to verify α-defensin 1-3 protein expression in mononuclear cells from peripheral blood and skin infiltrates. α-Defensin 1-3 concentration was evaluated in plasma and blister fluid samples by ELISA. We herein describe DEFA1A3 gene expression in peripheral blood mononuclear cells (PBMCs) from patients with drug-induced cutaneous diseases. Gene expression analysis unveiled transcription in CD4 and CD8 peripheral blood T cells. Protein expression was confirmed by intracellular flow cytometry in mononuclear cells from the patients, including monocytes, NK cells, and T cells from peripheral blood and blister fluid. Further analysis of protein content by flow cytometry revealed higher protein levels in CD56(+) CD3(+) lymphocytes from patients with SJS/TEN when compared to MPE and healthy donors. Immunohistological analysis was used to confirm expression in dermal infiltrates. α-Defensin levels were estimated by ELISA to be 3- to 175-fold higher in blister fluid when compared to simultaneously drawn plasma samples. Upregulation of innate immune molecules such as α-defensins 1-3 in T cells from patients with SJS/TEN may be involved in the etiopathology of these life-threatening diseases induced by medications.

Cytokine and chemokine expression in the skin from patients with maculopapular exanthema to drugs

Maculopapular exanthema (MPE) is the most frequent clinical manifestation of nonimmediate allergic reactions to drugs and T helper 1 (Th1) cytokines and CD4(+) T cells have been shown to play an important role in its pathogenesis. We assessed the role of cytokines and chemokines and their receptors in the pathogenesis of MPE. We evaluated skin biopsies and peripheral CD4(+) and CD8(+) T cells from 27 patients during the acute phase of the reaction and 26 exposed controls. Semiquantitative real-time PCR was performed to determine the expression of cytokines and chemokines and their receptors and immunohistochemistry was used to determine the same chemokines and their receptor proteins in skin. There was a high expression of the Th1 cytokines interferon-gamma (P = 0.006) and tumor necrosis factor-alpha (P = 0.022) in skin and CD4(+) T cells (P = 0.007 and P = 0.005, respectively); and of the Th1 chemokines CXCL9 (P = 0.005) and CXCL10 (P = 0.028) in the skin, while their receptor CXCR3 was increased in skin (P = 0.006) and CD4(+) T cells (P = 0.03). Homing chemokine receptors were also increased: CCR6 in skin (P = 0.026) and CD4(+) T cells (P = 0.016), and CCR10 only in CD4(+) T cells (P = 0.016), as well as their ligands, CCL20 and CCL27, in skin alone. Immunohistochemistry confirmed these results. These data show significant differences in the expression of chemokines and chemokine receptors, related with a Th1 profile, in both skin biopsies and peripheral CD4(+) T cells in patients with drug-induced MPE.

Role of Effector Cells In Drug-induced Maculopapular Exanthema

Role of Effector Cells In Drug-induced Maculopapular Exanthema

Immunohistology of drug-induced exanthema: clues to pathogenesis.

Hypersensitivity reactions to drugs can cause a variety of different skin disorders, the most frequent being maculopapular eruptions. In recent years increasing evidence has indicated the important involvement of T cells in this drug reaction. Histopathological changes typically show a dominant T-cell infiltration together with vacuolar interface dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and CD8+ T cells, which contain perforin and granzyme B, in close proximity to keratinocytes showing signs of cell destruction. Expression of Fas ligand is barely detectable, which suggests that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. In addition, drug-specific T cells may orchestrate the inflammatory skin reaction through the release and induction of various cytokines (i.e. IL-5, IL-6, TNF-alpha, IFN-gamma) and chemokines (i.e. regulated on activation, normal T-cell expressed and secreted; eotaxin). These mediators contribute to the generation of eosinophilia, which may amplify the underlying immune response through the release of further proinflammatory mediators in drug-induced maculopapular exanthema.

Pathogenesis of Drug-Induced Exanthema

Background: In vitro data derived from drug-specific T cell clones have revealed that heterogeneous T cell subsets with distinct phenotypes (CD4+ > CD8+) and cell functions (strong IL-5 production, cytotoxic potential) are generated. The aim of this study was to elaborate the relevance of these findings in vivo. Methods: Skin biopsy specimens from drug-induced maculopapular exanthema and normal skin were analyzed for CD4, CD8, CD25, HLA-DR, CD54, perforin, granzyme B, IL-5 and IFN-γ using immunohistochemistry. Results: The majority of infiltrating lymphocytes in maculopapular drug eruptions were CD4+. Both CD4+ and CD8+ T cells expressed perforin and granzyme B and were partly located at the dermoepidermal junction and in the epidermis. In addition, strong immunoreactivity for IL-5 and moderate immunoreactivity for IFN-γ were observed in the mononuclear cell infiltrate. Conclusions: Our data indicate that skin infiltrating T cells with a cytotoxic potential and the ability to produce IL-5 and IFN-γ may contribute to the damage of keratinocytes and the activation of eosinophils, which are typical features of drug-induced maculopapular exanthema.