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. 2017 Sep 22;4(4):ofx202.
doi: 10.1093/ofid/ofx202. eCollection 2017 Fall.

Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

Ofer Zimmerman  1 , Berenice Rösler  2 , Christa S Zerbe  1 , Lindsey B Rosen  1 , Amy P Hsu  1 , Gulbu Uzel  1 , Alexandra F Freeman  1 , Elizabeth P Sampaio  1 , Sergio D Rosenzweig  3 , Hye Sun Kuehn  3 , Tiffany Kim  4 , Kristina M Brooks  4 , Parag Kumar  4 , Xiaowen Wang  2   5 , Mihai G Netea  2 , Frank L van de Veerdonk  2 , Steven M Holland  1
Affiliations

Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

Ofer Zimmerman et al. Open Forum Infect Dis. .

Abstract

Heterozygous STAT1 gain-of-function (GOF) mutations are associated with chronic mucocutaneous candidiasis and a broad spectrum of infectious, inflammatory, and vascular manifestations. We describe therapeutic failures with the Janus Kinase (JAK) inhibitor ruxolitinib in 2 STAT1 GOF patients with severe invasive or cutaneous fungal infections.

Keywords: STAT1; coccidiomycosis; dermatophytosis; gain of function; ruxolitinib.

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Figures

Figure 1.
Figure 1.
Skin lesions of patient 1 before treatment (A1) and after 4 weeks of oral ruxolitinib treatment (A2). (B) Ex vivo whole blood CD14+ cells pSTAT1 level in patient 4 (red lines), at rest and up to 120’ after IFNγ stimulation, compared with 3 different healthy controls (blue lines). Assays were performed when the patient was ruxolitinib naïve (B1), treated with 20 mg ruxolitinib BID (B2), and treated with 10 mg ruxolitinib BID (B3). (C1) Patient 4’s (red bars) and a controls’ (n = 3, blue bars) CD14+ cells pSTAT1 levels with IFNγ 15’ stimulation, with and without ruxolitinib pre-incubation at increasing concentrations. pSTAT1 levels are expressed in percentages of each individual’s STAT1 phosphorylation with IFNγ stimulation with no ruxolitinib pre-incubation. (C2) Patient 4’s (red bars) and a control’s (blue bars) CD14+ pSTAT1 levels at rest and with IFNγ stimulation, with and without ruxolitinib pre-incubation. IP-10 (D1) and MIG (D2) secretion level (pg/mL) of patients 4 and 5 (red bars) and healthy controls’ (n = 3; blue bars) PBMCs stimulated with IFNγ 400 U/mL for 24 hours, after pre-incubation with ruxolitinib at increasing concentrations. Abbreviation: AUC, area under the curve.
See this image and copyright information in PMC

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