Inhaled steroids associated with decreased macrophage markers in nonasthmatic individuals with sickle cell disease in a randomized trial

Abstract

Inhaled mometasone was shown to improve pain scores and decrease soluble vascular cell adhesion molecule (sVCAM) concentration in a randomized controlled trial of nonasthmatic patients with sickle cell disease. We sought to explore potential changes in systemic inflammation as a mechanism underlying this effect. Serum samples from 41 trial participants (15 placebo- and 26 mometasone-treated) were analyzed using a 92 inflammatory marker panel at baseline and after 8 weeks of mometasone therapy. Individual marker analysis and correlation analysis were conducted. Adjusted for age, the mometasone-treated group decreased the concentration of CXCL9, CXCL11, CD40, IL-10, and IL-18 relative to placebo-treated participants. Hierarchical clustering and correlation analysis identified additional evidence for a decrease in cytokines linking to macrophage signaling and migration. There was no statistically significant change in markers of asthma and allergy, indicating that the improvement was unlikely mediated by modulation of occult reactive airway disease. This analysis of inflammatory markers suggests that decrease in macrophage activity may be involved in the mediation of the clinical benefit seen with use of inhaled mometasone in nonasthmatic patients with sickle cell disease.Trial registration: clinicaltrials.gov identifier: NCT02061202.

Keywords: Hemoglobinopathies; Inhaled corticosteroids; Macrophage activation; Sickle cell disease.

Figure 1:. Patient Flow CONSORT Diagram.

Among those individuals randomized, lack of adherence to therapy excluded eight patients from the mometasone group and one from the placebo group. Two additional individuals in each group were not included in analysis due to lack of serum sample availability.

Figure 2:. Hierarchical clustering of patients by post-treatment analyte signature demonstrates grouping based on treatment.

Heatmap of percent-differences in O-link analyte measurements post-treatment with either inhaled mometasone (orange) or placebo (purple). Patients and analytes are ordered by complete-linkage hierarchical clustering according to spearman-correlation distance. Based on the clustering of increases (red) and decreases (blue) in analytes, the majority of patients treated with mometasone are able to be segregated from those who received placebo. This is primary driven by markers associated with mononuclear phagocytes.

Figure 3:. Correlation analysis reveals disease-associated analyte modules.

Heatmap of spearman-correlation values of post-treatment percent-differences in analyte measurements. Analytes are ordered by complete-linkage hierarchical clustering.