The systemic treatments for drug reaction with eosinophilia and systemic symptoms (DRESS) beyond corticosteroids

Abstract

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe type of cutaneous adverse reaction. The gold standard therapy for DRESS involves the discontinuation of the culprit drug, supportive therapies, and administration of corticosteroids. However, in cases of primary treatment failure or suboptimal response, there arises an urgent need for alternative interventions. This review focuses on exploring alternative systemic therapies for patients with steroid-resistant DRESS, steroid-dependent DRESS, or refractory DRESS, encompassing immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, biologics, and small molecule drugs, with an emphasis on their clinical efficacy and the underlying mechanisms in the treatment of DRESS. Furthermore, this review provides a summary of potential management strategies and laboratory workup during the treatment of DRESS.

Keywords: Corticosteroid; Cyclosporine; Drug reaction with eosinophilia and systemic symptoms; Drug-induced hypersensitivity syndrome; IL-5/IL-5R inhibitors.

Fig. 1

The schematic mechanisms of cyclosporine on T cells. Figure notes: First, cyclosporine A forms a complex in the cytoplasm by binding to its immunophilin, cyclophilin A. Following this interaction, the complex effectively inhibits the activity of the Ca²⁺-dependent phosphatase calcineurin, which is characterized by its serine/threonine phosphatase activity. Consequently, the cytoplasmic component of the nuclear factor of activated T cells (NF-ATc) fails to be dephosphorylated due to the absence of calcineurin phosphatase activity. Thereby NF-ATc fails to transport from the cytoplasm to the nucleus and bind to the nuclear component of the nuclear factor of activated T cells (NF-ATn). NF-ATn is responsible for binding to the promoter region of the interleukin 2 (IL-2) gene, consequently initiating IL-2 production. Therefore, T cells are unable to produce IL-2, which is essential for full T-cell activation. Abbreviations: IL-2, interleukin 2; NF-ATc, the cytoplasmic component of the nuclear factor of activated T cells; NF-ATn, the nuclear component of the nuclear factor of activated T cells

Fig. 2

The schematic mechanisms of IL-5/IL-5R inhibitors and their downstream signal pathways. Figure notes: Mainly derived from T cell and mast cell, interleukin-5 (IL-5) acts on eosinophils and closely related basophil lineages in humans. In eosinophils, IL-5 can bind to its membrane receptor composed of a ligand-specific α subunit (IL-5Rα) and a nonspecific signaling βc subunit and thereby triggers down-stream signal transduction probably via dimerization of the cytoplasmic domain. The activated signaling pathways involve several transducing enzymes, mainly including Janus kinases (JAK), JAK/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), the extracellular signal-regulated kinases (ERK1 and ERK2), Lyn tyrosine kinase, phosphoinositide 3-kinase, and nuclear factor κB (NF-κB), which play a vital role in eosinophil differentiation, proliferation, and survival. Mepolizumab is an IgG1κ antibody against interleukin-5 (IL-5), while reslizumab is an IgG4κ antibody against IL-5, and hence they exhibit differences in their Fc biologic activity. Benralizumab targets and binds to the α subunit of IL-5R, preventing eosinophil signal transduction. Abbreviations: IL-5, interleukin-5; IL-5R, interleukin-5 receptor; ERK, extracellular signal-regulated kinases; JAB, JAK-binding protein; JAK, Janus kinases; MAPK, mitogen-activated protein kinase; MEK, MAP or ERK kinase; NF-κB, nuclear factor kappa B; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; Raf-1, v-raf-1 murine leukaemia viral oncogene homologue 1; Ras, Ras GTPase; STAT, signal transducer and activator of transcription

Fig. 3

Management of DRESS patients based on current scientific evidence. Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; CS, corticosteroid; CMV, cytomegalovirus; MMF, mycophenolate mofetil; IVIG, intravenous immunoglobulin