Treatment of Hypereosinophilic Syndrome with Cutaneous Involvement with the JAK Inhibitors Tofacitinib and Ruxolitinib

Abstract

Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders characterized by persistent peripheral blood eosinophilia, eosinophil-mediated end-organ damage, and absence of other infectious or allergic causes of eosinophilia.(Gotlib, 2014, Valent et al., 2012) Treatment of HES is challenging and usually relies on corticosteroids, which have significant adverse effects.(Klion, 2015, Klion et al., 2006) There are 3 categories of HES: primary, secondary, and idiopathic. Primary HES is a myeloproliferative disease with clonal eosinophils. In secondary HES and idiopathic HES, other cells produce Th2 cytokines that promote polyclonal expansion and activation of eosinophils.(Roufosse, Cogan and Goldman, 2007) Lymphocytic variant HES (L-HES) is a subtype of secondary HES wherein the source of Th2 cytokines is a phenotypically abnormal CD4+ T cell (typically CD3-CD4+).(Simon, Plotz, Dummer and Blaser, 1999, Walker et al., 2015) We recently demonstrated the importance of Janus kinase-Signal transducer and activation of transcription (JAK-STAT) signaling in L-HES.(Walker, et al., 2015) Specifically, we showed a gain-of-function mutation in STAT3 and overexpression of STAT3 gene targets that were necessary and sufficient for the production of eosinophil-promoting Th2 cytokines. Based on these data, we hypothesized that inhibitors of this pathway, namely the JAK inhibitors tofacitinib (JAK1/3 inhibitor) and ruxolitinib (JAK1/2 inhibitor), would be effective treatment of secondary HES.