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.

Trial registration: ClinicalTrials.gov NCT00001406 NCT01524536 NCT00090662.

Keywords: eosinophil; eosinophilia; glucocorticoid receptor; steroid.

Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Figures

Figure 1.. Cellular response to GC in HES.

Untreated subjects with HES were given a single dose of prednisone (1mg/kg) followed by prednisone (30 mg) daily for one week. (A-C) AEC, ANC, and ALC prior to and at 1 week following initiation of prednisone (D) Percent of baseline absolute cell counts at 1 week following initiation of prednisone. Symbols represent individual subject data (GC-sensitive (s; n=19; open black circles) and GC-resistant (r; n=8; closed gray circles). Solid horizontal lines indicate the GMs. The dotted horizontal line in panel D indicates 100% of baseline (no change). *p

Figure 2.. Alternations in mRNA expression of GR splice variants do not explain GC resistance in HES.

(A, B) mRNA expression of GRα, GRβ, GRP and GRγ isoforms in purified eosinophils or PBMC expressed as 1/ΔCt using 18S as a control (C, D) the ratio of GRβ, GRP and GRγ isoform mRNA expression to GRα mRNA expression in purified eosinophils or PBMC. Symbols represent the values from individual healthy controls (h; closed black circles); GC-sensitive patients with HES (s; open black circles) and GC-resistant patients with HES (r; closed gray circles). The horizontal lines denote the geometric means for each group. *p < 0.05

Figure 3.. Baseline serum cytokine levels in GC-sensitive and GC-resistant subjects.

Symbols represent the values from individual healthy controls (h; closed black circles); GC-sensitive patients with HES (s; open black circles) and GC-resistant patients with HES (r; closed gray circles). The horizontal lines denote the geometric means for each group. *p