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

INTRODUCTION

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.

RESULTS and DISCUSSION

Five patients with either idiopathic HES with cutaneous involvement or L-HES were included in this study (Table 1, Figure S1). We evaluated the patients for evidence of other diseases in the differential diagnosis. No patient had any pathologic or molecular evidence of myeloproliferative neoplasm. No patient had onset of disease in infancy or atopy. The immunohistochemical findings were inconsistent with atopic dermatitis, urticaria, or vasculitis. All had been treated with prednisone with inadequate suppression of cutaneous disease and pruritus at a dose of 10 mg daily.

Table 1.

Patient demographics, disease characteristics, and treatment

Patient	Age, gender	HES duration, years	HES type	Blood eosinophil count, cells/mm3, prior to treatment1	Blood eosinophil count, cells/mm3, taking prednisone 10 mg daily1	Blood eosinophil count, cells/mm3, taking tofacitinib or ruxolitinib1,3	Follow-up period taking tofacitinib or ruxolitinib, months3	Cutaneous disease and pruritus before and after tofacitinib or ruxolitinib monotherapy	Adverse effects of tofacitinib or ruxolitinib	Prior treatments
1	29, male	2	L-HES with cutaneous involvement	2,194	815	438	13	Before: Erythematous, edematous papules and plaques involving the arms and legs Severe pruritus After: Clear (no skin lesions) No pruritus	Upper respiratory infection	prednisone
2	61, female	31	L-HES with cutaneous involvement	2,819	1,714	825	3	Before: Eczematous dermatitis and lichenified plaques involving the face, neck, forearms, hands, lower legs, dorsal feet Moderate pruritus After: Very mild eczematous dermatitis involving the face Mild pruritus	None	prednisone, mycophenolate mofetil, extracorporeal photopheresis
3	44, female	4	Idiopathic HES with cutaneous involvement	2,147	1,325	308	6	Before: Erythematous, edematous plaques involving the chest, abdomen, forearms, lower legs Severe pruritus After: Erythema involving the bilateral shins No pruritus	Urinary tract infection, furuncle	prednisone, mycophenolate mofetil, methotrexate
4	73, female	2	Idiopathic HES with cutaneous involvement	1,936	1,116	88	7	Before: Eczematous dermatitis involving the head, neck, chest, abdomen, back, buttocks, arms, legs (95% body surface area) Severe pruritus After: Clear (no skin lesions) No pruritus	Episode of herpes simplex virus reactivation	prednisone, mycophenolate mofetil, methotrexate, cyclosporine
5	52, male	8	Idiopathic HES with cutaneous involvement	1,536	–2	578	9	Before: Eczematous dermatitis involving the chest, abdomen, back, arms, legs (50% body surface area) Moderate-severe pruritus After: Clear (no skin lesions) No pruritus	None	prednisone

HES indicates hypereosinophilic syndrome; L-HES, lymphocytic variant hypereosinophilic syndrome

¹Blood eosinophil count is the average of 3 or more values measured during a 3–18 month period except for patients 3 and 4 for whom there were only 2 measurements taking prednisone 10 mg daily.

²Blood eosinophil count during treatment with prednisone 10 mg daily was not documented for patient 5, but at a dose of 60 mg daily the value was 0 (cells/mm³).

³Values are for tofacitinib or ruxolitinib monotherapy except for patient 2 who required prednisone 5 mg daily together with tofacitinib.

In 2 patients peripheral blood flow cytometry revealed a monoclonal population of CD3-CD4+CD8-CD7dim/-CD5+CD2+ T cells comprising 1–5% of total cells, consistent with a diagnosis of L-HES. These patients (patients 1 and 2) had previously undergone RNA-Seq analysis of CD3-CD4+ cells, revealing activation of STAT3, STAT3 target genes, and Th2 cytokines in the phenotypically abnormal T cells (Walker, et al., 2015). The other 3 patients had idiopathic HES.

Remission or near-remission of clinical disease without the concomitant use of prednisone was achieved with tofacitinib 5mg twice daily in 3 patients (patients 1, 4, 5) and with ruxolitinib 25mg in the morning and 10mg at night in one patient (patient 3); one patient (patient 2) required prednisone 5mg daily in addition to tofacitinib 5mg twice daily. Figure 1b shows resolution of erythroderma in patient 4 on tofacitinib 5mg twice daily.

Figure 1. Blood eosinophil count and clinical response to treatment.

(a) Blood eosinophil counts decreased significantly on prednisone 10 mg daily and decreased further on tofacitinib or ruxolitinib. (b) Eczematous dermatitis confluent over the thighs in patient 4, who was erythrodermic prior to treatment, remitted during treatment with tofacitinib.

Blood eosinophil counts decreased dramatically, normalizing in the 4 patients who achieved corticosteroid-sparing monotherapy and nearly normalizing in patient 2 who required a low-dose of prednisone to achieve remission of clinical disease (Table 1, Figure 1a). The pre-treatment mean blood eosinophil count was 2,135/mm³ (median 2,147/mm³). On prednisone 10mg daily, the mean blood eosinophil count was 1,260/mm³ (median 1,255/mm³). On tofacitinib or ruxolitinib, the mean blood eosinophil count, 462/mm³ (median 438/mm³) was markedly lower than pre-treatment (P=0.0008; paired two-sided student’s t-test).

Adverse events were limited to minor infections (Table 1). There were no instances of cytopenia, transaminitis, decreased renal function, or increased lipid levels. The median follow-up period on tofacitinib or ruxolitinib monotherapy was 8 months (range 6–13 months).

Our recent report suggests that JAK-STAT signaling is a therapeutic target in secondary HES.(Walker et al, 2015) JAK1 signaling, in particular, leads to activation of STAT3 and STAT3 target genes critical for Th2 differentiation; therefore, JAK1 inhibition should suppress disease. Preclinical studies suggest that genetic or pharmacologic inhibition of these molecules abolishes both Th2 differentiation and the production of eosinophil-promoting cytokines such as IL-4, IL-5, and IL-13.(Keohane et al., 2015, Stritesky et al., 2011) The results of our therapeutic trial suggest that JAK inhibitors, tofacitinib and ruxolitinib, can be effective for the treatment of HES with cutaneous involvement, resulting in normalization of blood eosinophil counts and remission of clinical disease without corticosteroids.

METHODS

Patients

Patients with skin rash and hypereosinophilia (defined according to World Health Organization (WHO) as absolute eosinophil count >1500/mm³ on ≥2 occasions for ≥1month(Gotlib, 2014, Valentet al., 2012)) were evaluated at a tertiary care center from September 2014 to February 2016. Patients were diagnosed with HES according to criteria established by the WHO(Gotlib, 2014) and the Year 2011 Working Conference on Eosinophil Disorders and Syndrome(Valentet al., 2012) (i.e., hypereosinophilia with end-organ infiltration and damage by eosinophils, and with secondary causes of eosinophilia, e.g., eczema, asthma, drug hypersensitivity, parasite infection, ruled-out). Evaluation included but was not limited to: medical history; review of medications; skin biopsy; complete blood count and differential; complete metabolic panel; immunoglobulin E; bone marrow biopsy and aspirate; peripheral blood and bone marrow cytogenetics; peripheral blood and bone marrow fluorescence in-situ hybridization for abnormalities of PDGFRA, PDGFRB, 7q, myc, or 20q; polymerase chain reaction of peripheral blood for bcr-abl, JAK2 V617F, and c-kit D816V; peripheral blood flow cytometry for abnormal lymphocyte subsets; and Strongyloides IgG antibody titre.

Patients with rash, eosinophilia, absence of myeloproliferative neoplasm, negative laboratory testing for secondary hypereosinophilic conditions, and either skin biopsy demonstrating infiltration by eosinophils or bone marrow biopsy showing >20% eosinophils were defined as having idiopathic HES with cutaneous involvement. Those with an abnormal population of circulating CD3-CD4+ T cells on flow cytometry were diagnosed with L-HES.

Treatment

Patients were started on tofacitinib 5mg twice daily. One patient (patient 3) was transitioned to ruxolitinib due to insurance reasons. Due to the severity of their pruritus, 3 patients (patients 1, 2, and 4) initially received tofacitinib in combination with prednisone, and the prednisone was subsequently tapered and discontinued over 1–6 months; due to a flare of her skin disease 5 weeks later, patient 2 was restarted and maintained on prednisone 5mg daily. Patients gave verbal consent for treatment (neither Institutional Review Board approval nor written consent were necessary).

Response to Treatment with Tofacitinib or Ruxolitinib

Response to treatment was assessed by decreases in blood eosinophil count, improvement in clinical disease (dermatitis, papules and plaques, and pruritus), and ability to reduce or discontinue corticosteroid use.

Supplementary Material

supplement. Figure S1. Clinical images prior to treatment.

Patient 1, Erythematous, edematous papules and plaques involving the thighs. Patient 2, Eczematous dermatitis and lichenified plaques involving the face. Patient 3, Erythematous, edematous plaque involving the forearm. Patient 4, Eczematous dermatitis involving the thighs. Patient 5, Eczematous dermatitis involving the back and flank. Patients gave permission to publish photographs.

Abbreviations

JAK

Janus kinase

HES

hypereosinophilic syndrome