Mechanisms of glucocorticoid resistance in hypereosinophilic syndromes

Abstract

Background Glucocorticoids (GC) are considered first‐line therapy for most patients with hypereosinophilic syndrome (HES). Although response rates are generally high, many patients require moderate to high doses for control of eosinophilia and symptoms, and up to 15% of patients do not respond at all. Despite this, little is known about the mechanisms of GC resistance in patients with HES. Objective To explore the aetiology of GC resistance in HES. Methods Clinical data and samples from 26 patients with HES enrolled on a prospective study of GC responsiveness and 23 patients with HES enrolled on a natural history study of eosinophilia for whom response to GC was known were analysed retrospectively. Expression of GC receptor isoforms was assessed by quantitative RT‐PCR in purified eosinophils. Serum cytokine levels were quantified by suspension array assay in multiplex. Results Despite an impaired eosinophil response to GC after 7 days of treatment, the expected rise in absolute neutrophil count was seen in 7/7 GC‐resistant patients, suggesting that GC resistance in HES is not a global phenomenon. Eosinophil mRNA expression of glucocorticoid receptor (GR) isoforms (α, β, and P) was similar between GC‐sensitive (n = 20) and GC‐resistant (n = 9) patients with HES. Whereas geometric mean serum levels were also comparable between GC‐r (n = 11) and GC‐s (n = 19) for all cytokines tested, serum IL‐5 levels were >100 pg/mL only in GC‐r patients. Conclusions and Clinical Relevance These data suggest that the mechanism of GC resistance in HES is not due to a global phenomenon affecting all lineages, but may be due, at least in some patients, to impairment of eosinophil apoptosis by increased levels of IL‐5.

A Lymphocytic Variant of Hypereosinophilic Syndrome Presenting With Isolated Cutaneous Manifestations

“…Although response rates to glucocorticoids are generally high, 15% of patients do not respond at all [8], which is the case in our patient. Stokes et al suggest that increased serum IL-5 may lead to glucocorticoid resistance in some patients with HES by impairing glucocorticoid-induced eosinophil apoptosis [8]. So, If a steroid-sparing therapy is needed, because of corticosteroid dependency or resistance, interferon-α, cyclosporin A, hydroxycarbamide, imatinib, and mepolizumab are appropriate therapeutic choices to control clinical manifestations and HE and sparing steroid consumption [6,9].…”

“…Corticosteroids are the first therapeutic line in treating CD3-CD4+ L-HES [6,7]. Although response rates to glucocorticoids are generally high, 15% of patients do not respond at all [8], which is the case in our patient. Stokes et al suggest that increased serum IL-5 may lead to glucocorticoid resistance in some patients with HES by impairing glucocorticoid-induced eosinophil apoptosis [8].…”

Developments allergy in 2019 through the eyes of clinical and experimental allergy, part I mechanisms

“…Other work examined eosinophils in order to address mechanisms of glucocorticoid (GC) resistance in non‐myeloid hypereosinophilic syndromes (HES). That report found no differences in GC receptor isoforms that might explain GC resistance based on a comparison of mRNA expression levels in eosinophils from GC‐resistant versus GC‐sensitive patients with HES 62 . However, elevated levels of serum IL‐5 in a subset of patients who were GC‐resistant raised an alternative theory wherein the actions of IL‐5 on eosinophils may serve to counter GC‐mediated eosinophil apoptosis.…”

“…That report found no differences in GC receptor isoforms that might explain GC resistance based on a comparison of mRNA expression levels in eosinophils from GC-resistant versus GC-sensitive patients with HES. 62 However, elevated levels of serum IL-5 in a subset of patients who were GC-resistant raised an alternative theory wherein the actions of IL-5 on eosinophils may serve to counter GC-mediated eosinophil apoptosis. Such variability in IL-5 levels across patients warrants further work to identify additional mechanisms of GC resistance.…”

Molecular mechanisms of glucocorticoid resistance

“…4 Different GR isoforms can be generated through selective splicing and translation initiation. 8 Alternative splicing of the C-terminal exon 9 of the primary GR transcript produces two highly homologous mRNA transcripts, resulting in two GR isoforms termed GRα and GRβ. 4 GRα is the most abundant isoform, and its function will be mentioned later.…”