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. 2023 Jun 21;159(8):820–829. doi: 10.1001/jamadermatol.2023.1651

Hyperactivation of the JAK2/STAT5 Signaling Pathway and Evaluation of Baricitinib Treatment Among Patients With Eosinophilic Cellulitis

Johanna Morot 1, Ester Del Duca 2, Marine Chastagner 1, Marie Fernandes 2, Yeriel Estrada 2, Marine-Alexia Lefevre 1, Jean Kanitakis 3,4, Olivier Harou 4, Denis Jullien 1, Jean-Francois Nicolas 1,5, James G Krueger 6, Marc Vocanson 1, Emma Guttman-Yassky 2, Axel P Villani 1,2,✉
PMCID: PMC10285679  PMID: 37342057

Key Points

Question

What are the molecular mechanisms underlying eosinophilic cellulitis (EC), and what are the potential treatment approaches for EC?

Findings

In this case series of 14 patients with EC, marked type 2 inflammation (chemokines CCL17, CCL18, and CCL26 and interleukin 13) with preferential activation of the signal transducer and activator of transcription STAT1 and STAT5 pathways was observed in EC lesions. In 1 index patient, treatment with baricitinib (a Janus kinase JAK1/JAK2 inhibitor) was associated with complete clinical remission of refractory EC, with normalization of the upregulated type 2 inflammation transcripts.

Meaning

These findings suggest that EC is a type 2 inflammatory disease with preferential activation of the JAK1/JAK2-STAT5 pathways, advocating for the development of treatment approaches targeting JAK1/JAK2.

This case series examines hyperactivation of the JAK2/STAT5 signaling pathway in patients with eosinophilic cellulitis and evaluates outcomes associated with baricitinib treatment.

Abstract

Importance

The pathogenesis of eosinophilic cellulitis (EC) is poorly understood, limiting available treatment options. The current treatment paradigm focuses on delayed type 2 hypersensitivity reaction to various triggers.

Objective

To gain further insight into the nature of EC inflammation and into the cellular signal transduction pathways that are activated in the context of EC.

Design, Setting, and Participants

This case series was conducted in Lyon, France, from January 2018 to December 2021. Analysis of archival skin biopsy samples from patients with EC and from healthy control participants was performed using histology, Janus kinase (JAK)–signal transducer and activator of transcription (STAT) immunohistochemistry, and gene profiling. Data analysis was conducted between January 2020 and January 2022.

Main Outcomes and Measures

Pruritus (visual analog score), percentage of body surface area with lesional skin, and RNA transcripts of inflammatory biomarkers from the skin (threshold cycle) were assessed in 1 index patient with refractory EC who received oral JAK1/JAK2 inhibitor baricitinib (4 mg/d).

Results

This study included samples from 14 patients with EC (7 men and 7 women) and 8 healthy control participants (4 men and 4 women). The mean (SD) age of patients was 52 (20) years. Marked type 2 inflammation (chemokines CCL17, CCL18, and CCL26 and interleukin 13) with preferential activation of the JAK1/JAK2–STAT5 pathways in EC lesions was observed. In the 1 index patient with refractory EC, complete clinical remission of skin lesions was observed after 1 month of treatment with baricitinib.

Conclusions and Relevance

These findings suggest that EC is a type 2 inflammatory disease with preferential activation of the JAK1/JAK2-STAT5 pathways. In addition, these results suggest the potential of treatment approaches targeting JAK1/JAK2 for patients with EC.

Introduction

Eosinophilic cellulitis (EC), also called Wells syndrome, is a rare eosinophilic dermatosis. Although clinical subtypes may exist within the EC spectrum, EC is typically characterized by fixed pruritic urticarial plaques, with blisters in the most severe cases.1,2 An EC diagnosis is based on histology, which reveals an intense eosinophilic infiltrate in the upper and mid dermis, and requires the exclusion of other autoimmune or paraneoplastic etiologies of skin eosinophilia.3

Treatment options for EC are limited. Although acute EC may resolve spontaneously, chronic and relapsing forms are treated with conventional immunosuppressants,4 which are associated with a high risk of adverse events and rare success.5,6,7 Promising clinical responses have been observed in a few case reports using anti–interleukin (IL)-5 or anti–IL-4 receptor α monoclonal antibody treatments.5,8,9,10,11

To date, the pathogenesis of EC is still poorly understood. The current paradigm suggests that it comprises a delayed helper T-cell type 2 (TH2) or type 2 hypersensitivity reaction to various endogenous and exogenous triggers such as viral and parasitic antigens, insect bites, medications, and vaccination.12,13 In this model, the interaction of type 2 cytokines with their cell surface receptors on target cells induces the phosphorylation of tyrosine residues on receptor-associated proteins, including Janus kinase JAK1/JAK2 and signal transducer and activator of transcription STAT1/STAT5, which activates downstream signaling molecules14 and leads to the production of mediators responsible for eosinophilic activation and recruitment into the skin.15,16

To gain further insight into the nature of EC inflammation and into the cellular signal transduction pathways that are activated in the context of EC, we conducted an analysis of skin biopsies from patients with EC using histology, JAK/STAT immunohistochemistry, and gene profiling. Marked type 2 inflammation was observed (typified by overexpression of IL-13 and chemokines CCL17, CCL18, and CCL26) and highlighted preferential activation of the JAK1/JAK2 and STAT5 pathways in EC lesions.17 Based on these observations, we treated a patient with long-standing refractory EC with an oral JAK1/JAK2 inhibitor (baricitinib).

Methods

This case series was reviewed and approved by the local ethics committee of the Hospices Civils de Lyon. For patients with archival samples, informed consent was waived because of the retrospective nature of the study and because the analysis used anonymous clinical data. Informed consent was obtained from the 1 index patient.

Analysis of Paraffin-Embedded Deidentified EC Samples

Deidentified skin lesion samples (including paraffin-embedded skin sections) from 14 patients with EC and 8 healthy control participants were obtained from archival material. An EC diagnosis was established on the basis of typical clinical lesions, histologic findings (inflammatory dermal skin infiltrate with eosinophils and sometimes flame figures), and chronic course and after exclusion of differential diagnoses (cancer, autoimmune disorders, hematologic neoplasms).

Prospective Investigation

An index patient with chronic EC refractory to various treatments, including oral prednisone, subcutaneous methotrexate, oral dapsone, and oral cyclosporine, received off-label treatment with baricitinib. The Dermatology Life Quality Index (score range, 0-30) and the percentage of body surface area (0%-100%) of lesional skin were used to gauge the severity of EC and the clinical response to the different medications. Five-millimeter punch biopsies were collected from lesional, nonlesional, and healed skin before and 1 month after baricitinib treatment (4 mg/d).

Reverse Transcription, Quantitative Real-time Polymerase Chain Reaction, and Gene Array Analysis

Total RNA was extracted from paraffin-embedded skin biopsy sections using the RNeasy formalin-fixed paraffin-embedded kit and from frozen skin biopsies using the RNeasy Mini Kit (both Qiagen). Tissues were crushed using a gentleMACS Dissociator (Miltenyi Biotec).

For archival samples, reverse transcription to complementary DNA (cDNA) from RNA was carried out using the High-Capacity cDNA Reverse Transcription Kit and cDNA was amplified with TaqMan Gene Expression Master Mix (both Applied Biosystems). TaqMan low-density array cards were used for the exploratory patient and for archival samples. Expression values (threshold cycle) were normalized to the hARP housekeeping gene and log2 transformed for analysis. All primers used for exploratory and archival samples are listed in eTable 1 in Supplement 1.

For the index patient, reverse transcription was done using random primers, deoxynucleoside triphosphate, Superscript IV reverse transcriptase, and RNase OUT (all Invitrogen) on a Mastercycler Nexus Gradient thermal cycler (Eppendorf). Quantitative real-time polymerase chain reaction (qRT-PCR) was performed using FastStart Universal SYBR Green Master Mix (Roche) on a StepOnePlus PCR system (Thermo Fisher Scientific). All primers used for the index patient samples are listed in eTable 2 in Supplement 1.

Histologic and Immunohistochemical Testing

Skin sections from patients with EC and from healthy control participants were stained using a hematoxylin and eosin standard protocol. The mean (SD) numbers of lymphocytes, eosinophils, and other immune cell subsets (monocytes, macrophages, and histiocytes [MMHs]) were identified based on their morphology and quantified on 3 representative sections per patient (manual point-counting method). Some sections were tested for expression of JAK/STAT signaling using rabbit anti-human phosphorylated STAT1 (pSTAT1) (Tyr701, catalog No. 9167, dilution 1:200), pSTAT3 (Tyr705, catalog No. 9145; dilution 1:200), and pSTAT5 (Tyr694, catalog No. 9314, dilution 1:200) monoclonal antibodies (all Cell Signaling Technology) and the rabbit-specific horseradish peroxidase detection immunohistochemistry system (ab93705; Abcam), with AEC as the chromogen. The mean (SD) number of cells positive for pSTAT1, pSTAT3, and pSTAT5 staining was quantified on 3 representative sections per patient (manual point-counting method).

Statistical Analysis

Raw quantification cycle (Cq) values were calculated in SDS software, version 2.4 (Thermo Fisher Scientific), using automatic baseline and threshold settings. To minimize statistical confounding by high Cq values, values that were undetermined or greater than 35 were replaced with Cq = 35 for further analysis. Relative microRNA levels were expressed as 2−ΔCq. Data were analyzed using R, version 3.4.3 (R Project for Statistical Computing). The geNorm and NormFinder algorithms were obtained from the NormqPCR package in R. The MA plots were created with the affy package in R. Intraclass correlation coefficients between 2 normalization methods were calculated per sample in R using the irr package. A 2-way mixed-effects model (mean measures) and absolute agreement definition was used. Subsequently, the mean of all sample interclass correlation coefficients (95% CIs) between 2 normalization methods was calculated.

Quantitative variables are expressed as the mean (SEM). For statistical comparisons, P values were calculated using the 2-tailed independent t tests in Prism software, version 9 (GraphPad Software Inc); P < .05 was considered statistically significant. Correlation analyses were performed using the Pearson formula. Data analysis was conducted between January 2020 and January 2022.

Results

This study included samples from 14 patients with EC (7 men and 7 women) and from 8 healthy control participants (4 men and 4 women). The mean (SD) age of patients was 52 (20) years.

Lymphocyte and Eosinophil Infiltrate in EC Lesions

Histologic analysis of 11 EC biopsies showed that the skin lesions were characterized by a marked polymorphic inflammatory infiltrate (Figure 1A), with greater accumulation of the mean (SD) number of lymphocytes (240 [49] cells/mm2), eosinophils (155 [35] cells/mm2), and other MMHs (90 [30] cells/mm2) in the EC dermis compared with skin samples from 4 healthy control participants (Figure 1B). Degranulating eosinophils were observed in 2 of 11 skin samples.

Figure 1. Immune Cell Subsets in Eosinophilic Cellulitis (EC) Skin Lesions.

Figure 1.

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A, Representative hematoxylin and eosin–stained section of an EC lesion. The black arrows indicate a degranulating eosinophil. The different immune cell subsets (lymphocytes, eosinophils, and monocytes, macrophages, and histiocytes) were identified and quantified based on their morphology. B, Mean (SEM) number of immune cell subsets in the lesional skin of 11 patients with EC and 4 healthy control (HC) participants.

Type 2 Response in EC Inflammation

We next characterized the molecular signature of EC inflammation. To this end, we first analyzed the expression of 91 genes related to immune responses in the lesional skin of an exploratory patient with EC using a gene array (eTable 1 in Supplement 1). Of these, 64 messenger RNA transcripts were upregulated compared with their expression in the skin of a healthy control participant (Figure 2). The top 20 overexpressed genes comprised markers mainly associated with type 2 responses, including chemokines involved in the recruitment of TH2 cells and eosinophils such as CCL7, CCL17, CCL18, and CCL26 as well as IL-13. Of note, IL-5 was not upregulated in this patient. Several markers of innate inflammation (matrix metalloproteinase MMP12, S-100 binding gene S100A7/A8/A9/A12, IL-20, and IL-17C) were also overexpressed. In contrast, there was no differential expression in interferon γ (IFNG), IL-17A, or IL-22 transcripts, illustrating the preferential type 2 bias in this patient (Figure 2).

Figure 2. Heat Map of Relative Expression of 91 Genes in Lesional Skin of 1 Patient With Eosinophilic Cellulitis and 1 Healthy Control Participant, Using the TaqMan Low-Density Array Card Gene Array.

Figure 2.

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aThese genes were then analyzed on paraffin-embedded samples retrieved from 13 patients with eosinophilic cellulitis.

To confirm these findings, we next investigated paraffin-embedded skin biopsy sections of 13 additional patients with EC and 7 healthy control participants. We used qRT-PCR to analyze the induction of 12 overexpressed genes (CCL7, CCL17, CCL18, CCL26, interleukin 3 receptor [IL-3R], IL-4, IL-6, IL-13, IL-17C, IL-20, S100A8, and S100A9) and 4 downregulated markers (CXCL11, IFNG, IL-5, and IL-5R) found in the exploratory patient. Elevated expression of IL-13, IL-3R, CCL17, CCL18, CCL26, S100A8, and S100A9 transcripts was confirmed in the majority of EC samples compared with those from healthy control participants. In contrast, no modulation was detected for IL-6, IL-20, CCL7, IL-17C, IL-5, IL-5R, IFNG, and CXCL11 markers (Figure 3).

Figure 3. Relative Expression of 16 Messenger RNA (mRNA) Transcripts Related to Immune Responses Detected in Lesional Eosinophilic Cellulitis (EC) Skin and in Healthy Control (HC) Skin, as Measured by Quantitative Real-time Polymerase Chain Reaction.

Figure 3.

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Gene relative expression is expressed as 2−ΔCq. IFN indicates interferon; IL indicates interleukin; rq, relative quantity.

Activation of pSTAT5 and pSTAT1 in EC Lesions

As type 2 inflammation is associated with unique intracellular signaling pathways induced by the binding of cytokines and chemokines to their cell surface receptors, we next characterized the JAK/STAT pathways that were preferentially activated in EC. For this, we assessed the activation levels of receptor-associated kinases pSTAT1, pSTAT3, and pSTAT5 by immunohistochemistry using the paraffin-embedded skin biopsy sections from the 13 patients with EC and 7 healthy control participants (Figure 4A). All samples from patients with EC vs samples from healthy control participants were positive for pSTAT5 expression (mean [SD], 203 [56] vs 1 [0.7] positive cells/mm2; P < .001) and, to a lesser extent, for pSTAT1 (mean [SD], 133 [55] vs 0.2 [0.1] positive cells/mm2, P < .001). Comparatively, pSTAT3 staining was very mild or negative in both groups (mean [SD], 18 [5] vs 0.2 [0.2] positive cells/mm2; Figure 4B).

Figure 4. Accumulation of Phosphorylated STAT5 (pSTAT5)-Positive and pSTAT1-Positive Cells in Eosinophilic Cellulitis (EC) Lesions.

Figure 4.

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A, Representative pSTAT1-, pSTAT3-, and pSTAT5-stained skin sections (original magnification, ×100 for images and ×300 for insets). B, The mean (SD) number of positive cells was quantified and compared with healthy control (HC) skin. C, The number of eosinophils and lymphocytes present in EC lesions was compared with the number of pSTAT1-, pSTAT3-, and pSTAT5-positive cells. Respective correlation factors were calculated using the Pearson method. The coefficient of determination (r) and statistical significance are indicated for each correlation.

Of note, we observed a significant correlation between the numbers of skin-infiltrating eosinophils and pSTAT5-positive cells (r = 0.62; P = .04), but not pSTAT1 (r = 0.49) or pSTAT3 (r = −0.15). In contrast, no statistically significant correlation was detected for the number of skin-infiltrating lymphocytes (Figure 4C).

Outcomes of JAK1/JAK2 Inhibition in Refractory EC

A 54-year-old man with a 3-year history of EC was evaluated due to a lack of disease response to multiple treatments. Full-body computed tomography, blood testing, and direct immunofluorescence were performed to exclude potential differential diagnoses. Blood test results for total blood count, blood ionogram, creatinine levels, and hepatic enzymes were normal; antinuclear antibodies were negative. No linear immunoglobulin IgG, IgM, IgA, or C3 deposit was detected on direct immunofluorescence. On histopathologic examination, epidermal spongiosis and marked eosinophilic infiltrate were observed; immunohistochemistry revealed positive staining for pSTAT5 and pSTAT1 but not pSTAT3. Over a 3-year period, the patient’s cutaneous disease did not respond to highly potent topical steroids or successive medications (including oral prednisolone [1 mg/kg/d], hydroxychloroquine [400 mg/d], oral methotrexate [20 mg/wk], and cyclosporine [3 mg/kg/d], each administered for at least 3 months) before the treatment was considered as having failed. Dapsone (100 mg/d) was associated with induced-methemoglobinemia and dyspnea and had to be discontinued (Figure 5A). Approximately 60% of the patient’s body surface area was involved, and his pruritus visual analog score was 10 of 10 with major sleep disturbance (Figure 5A). With the patient’s consent and following approval by an academic multidisciplinary consensus committee, off-label treatment with baricitinib (4 mg/d), a JAK1/JAK2 inhibitor, was then initiated. Complete resolution of the patient’s skin lesions was observed at 1 month (Figure 5B). Skin samples were also obtained before (from lesional and nonlesional skin) and after 1 month of treatment (from healed skin) for qRT-PCR investigation (eTable 2 in Supplement 1). Before treatment, upregulation of several specific type 2 inflammatory cytokines (IL13, IL3, and IL4, but not IL5) and associated chemokines (CCL17, CCL18, and CCL26) was observed in lesional compared with nonlesional skin. After 1 month of treatment, most of the upregulated type 2 inflammation transcripts were completely normalized in the previously lesional and now clinically healed skin (Figure 5C).

Figure 5. Treatment History, Clinical Response, and Molecular Response With Baricitinib.

Figure 5.

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A, Time course and clinical response (top line: pruritus visual analog scale [VAS] score; bottom line: percentage of body surface area [BSA]) for 1 patient with eosinophilic cellulitis (EC) (index patient) treated with various medications, including prednisone (1 mg/kg/d), disulone (100 mg/d), methotrexate (15 mg/wk), cyclosporine (300 mg/d), and baricitinib (4 mg/d). B, Photographs of skin lesions of the index patient before and after 4 weeks of baricitinib therapy. C, Relative expression of 8 messenger RNA (mRNA) transcripts related to type 2 and type 1 immunity detected in the lesional skin (LS) and nonlesional skin (NLS) of the index patient before starting baricitinib as well as in the healed skin (HS) 4 weeks after treatment initiation. Gene expression was measured with quantitative real-time polymerase chain reaction and is expressed as log2(−ΔCq). IFNG indicates interferon γ; IL, interleukin; and rq, relative quantity.

Discussion

We herein report an in-depth characterization of EC skin inflammation and its association with a marked type 2 immune response and hyperactivation of the JAK2/STAT5 signaling pathway. In the skin of patients with EC, we detected expression of several eosinophil-related chemokines, such as CCL17, CCL18, and CCL26, and also of cytokine IL-13. Confirming the presence of a type 2 immune environment, we also detected upregulation of the IL3R messenger RNA transcript, together with an increased number of IL-3R–positive cells in EC lesional skin. Expression of IL-3R was recently shown to considerably increase in human TH2 cells activated in the presence of IL-4; in turn, IL-3R signaling then promotes TH2 cell differentiation.18 In contrast, although EC is considered a primary IL-5–induced disease, we did not observe notable expression of IL-5 or IL-5R transcripts in lesional skin. This does not exclude a role of IL-5 in the initiation of EC, because IL-5 expression may have been inhibited by secondary mediators,19 notably in chronic forms of EC.

The STAT5 pathway is critical for the maturation of both TH2 cells and eosinophils and their recruitment into tissues, in particular by mediating IL-5 and IL-13 expression.20,21,22 Gain-of-function mutations in STAT5 are associated with various clinical manifestations, including skin eosinophilia,23,24 hematologic neoplasms associated with eosinophilia,25,26,27 and some cases of hypereosinophilic syndrome.28 As EC is classified as a single-organ variant of the hypereosinophilic syndrome,29 a similar genetic predisposition could be the primary event in EC onset; the high activation of STAT5 would facilitate TH2 and eosinophil recruitment into the skin upon various environmental and cutaneous triggers. The STAT5 pathway could be further activated in an autocrine manner by IL-13,30,31 leading to a type 2 inflammatory loop.

Gain-of-function mutations in JAK1/STAT1 have also been reported in rare cases of hypereosinophilic syndrome.32 Consistently, the STAT1 pathway was also activated in EC lesional skin, but to a lesser extent than STAT5. This could be the result of shared cytokine drivers, such as IL-5 and IL-13, that are able to activate both pathways.33,34 In this study, pSTAT5, but not pSTAT1, staining was significantly correlated with the level of eosinophils infiltrating the skin in patients with EC, suggesting that pSTAT5 may be key to the recruitment or maintenance of eosinophils within the skin and that pSTAT1 activation may be secondary to the type 2 inflammation generated. Parallel to pSTAT5 and pSTAT1 activation, future studies should investigate the involvement of the STAT6 pathway in EC, as this pathway plays a major role in the differentiation of type 2 cytokine–producing cells.35

Consistent with the high activation levels of pSTAT5 and pSTAT1 detected in EC lesions, we targeted their respective JAK receptors (JAK236 and JAK137) using baricitinib. In this study, while the index patient’s EC was not responsive to various medications, prolonged clinical and molecular remission was observed after baricitinib treatment. Interestingly, baricitinib induces substantial downregulation of the pSTAT5 and pSTAT1 pathways in stimulated T cells and monocytes in vitro.38,39 Compared with other JAK inhibitors such as tofacitinib, treatment with baricitinib was also associated with full-spectrum inhibition of all stages of eosinophil development, potently inhibiting eosinophil chemotaxis and eosinophil differentiation/activation in a mouse model of eosinophilic asthma.38

Limitations

Although these findings are promising, a limitation of our study is that the response to baricitinib therapy was observed in only 1 patient with EC and needs to be replicated in other patients. Further studies are needed to understand the efficacy and safety of this treatment strategy in patients with refractory EC.

Conclusions

The findings of this case series suggest that EC may be a TH2-related inflammatory disease with marked JAK2/pSTAT5 activation, leading to the dysregulated recruitment of eosinophils in the skin. Together with the clinical response to baricitinib, our data advocate for the development of JAK1/JAK2 targeting treatment approaches in EC and other eosinophilic diseases.38,40,41

Supplement 1.

eTable 1. Primers Used in Analysis of Archival Samples

eTable 2. Primers Used in Analysis of Index Patient Samples

Click here for additional data file. (252.1KB, pdf)
Supplement 2.

Data Sharing Statement

Click here for additional data file. (15.9KB, pdf)

References

  • 1.Marzano AV, Genovese G. Eosinophilic dermatoses: recognition and management. Am J Clin Dermatol. 2020;21(4):525-539. doi: 10.1007/s40257-020-00520-4 [DOI] [PubMed] [Google Scholar]
  • 2.Caputo R, Marzano AV, Vezzoli P, Lunardon L. Wells syndrome in adults and children: a report of 19 cases. Arch Dermatol. 2006;142(9):1157-1161. doi: 10.1001/archderm.142.9.1157 [DOI] [PubMed] [Google Scholar]
  • 3.Moossavi M, Mehregan DR. Wells’ syndrome: a clinical and histopathologic review of seven cases. Int J Dermatol. 2003;42(1):62-67. doi: 10.1046/j.1365-4362.2003.01705.x [DOI] [PubMed] [Google Scholar]
  • 4.Räßler F, Lukács J, Elsner P. Treatment of eosinophilic cellulitis (Wells syndrome)—a systematic review. J Eur Acad Dermatol Venereol. 2016;30(9):1465-1479. doi: 10.1111/jdv.13706 [DOI] [PubMed] [Google Scholar]
  • 5.Terhorst-Molawi D, Altrichter S, Röwert J, et al. Effective treatment with mepolizumab in a patient with refractory Wells syndrome. J Dtsch Dermatol Ges. 2020;18(7):737-739. doi: 10.1111/ddg.14151 [DOI] [PubMed] [Google Scholar]
  • 6.Wallis L, Gilson RC, Gilson RT. Dapsone for recalcitrant eosinophilic annular erythema: a case report and literature review. Dermatol Ther (Heidelb). 2018;8(1):157-163. doi: 10.1007/s13555-017-0214-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Żychowska M, Tutka K, Reich A. Mepolizumab therapy for recalcitrant eosinophilic annular erythema in an adult: a case report and review of treatment options. Dermatol Ther (Heidelb). 2020;10(4):893-899. doi: 10.1007/s13555-020-00412-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Herout S, Bauer WM, Schuster C, Stingl G. Eosinophilic cellulitis (Wells syndrome) successfully treated with mepolizumab. JAAD Case Rep. 2018;4(6):548-550. doi: 10.1016/j.jdcr.2018.02.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Manka LA, Guntur VP, Denson JL, et al. Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis. Ann Allergy Asthma Immunol. 2021;126(6):696-701.e1. doi: 10.1016/j.anai.2021.01.035 [DOI] [PubMed] [Google Scholar]
  • 10.Agache I, Song Y, Posso M, et al. Efficacy and safety of dupilumab for moderate-to-severe atopic dermatitis: a systematic review for the EAACI biologicals guidelines. Allergy. 2021;76(1):45-58. doi: 10.1111/all.14510 [DOI] [PubMed] [Google Scholar]
  • 11.Traidl S, Angela Y, Kapp A, Suhling H, Schacht V, Werfel T. Dupilumab in eosinophilic cellulitis (Wells’ syndrome)—case report of a potential new treatment option. J Dtsch Dermatol Ges. 2021;19(11):1653-1655. doi: 10.1111/ddg.14598 [DOI] [PubMed] [Google Scholar]
  • 12.Koga C, Sugita K, Kabashima K, Matsuoka H, Nakamura M, Tokura Y. High responses of peripheral lymphocytes to mosquito salivary gland extracts in patients with Wells syndrome. J Am Acad Dermatol. 2010;63(1):160-161. doi: 10.1016/j.jaad.2009.08.041 [DOI] [PubMed] [Google Scholar]
  • 13.Mashima E, Sawada Y, Yamaguchi T, et al. Eosinophilic cellulitis possibly due to mosquito bite with high IL-5 production. J Investig Allergol Clin Immunol. 2017;27(2):149-150. doi: 10.18176/jiaci.0142 [DOI] [PubMed] [Google Scholar]
  • 14.Takatsu K. Interleukin-5 and IL-5 receptor in health and diseases. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(8):463-485. doi: 10.2183/pjab.87.463 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Plötz SG, Abeck D, Behrendt H, Simon HU, Ring J. Eosinophilic cellulitis (Wells syndrome). Article in German. Hautarzt. 2000;51(3):182-186. doi: 10.1007/s001050051101 [DOI] [PubMed] [Google Scholar]
  • 16.French LE, Shapiro M, Junkins-Hopkins JM, Wolfe JT, Rook AH. Eosinophilic fasciitis and eosinophilic cellulitis in a patient with abnormal circulating clonal T cells: increased production of interleukin 5 and inhibition by interferon alfa. J Am Acad Dermatol. 2003;49(6):1170-1174. doi: 10.1016/S0190-9622(03)00447-X [DOI] [PubMed] [Google Scholar]
  • 17.Traves PG, Murray B, Campigotto F, Galien R, Meng A, Di Paolo JA. JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib. Ann Rheum Dis. 2021;80(7):865-875. doi: 10.1136/annrheumdis-2020-219012 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Kumar A, Rani L, Mhaske ST, et al. IL-3 receptor expression on activated human Th cells is regulated by IL-4, and IL-3 synergizes with IL-4 to enhance Th2 cell differentiation. J Immunol. 2020;204(4):819-831. doi: 10.4049/jimmunol.1801629 [DOI] [PubMed] [Google Scholar]
  • 19.Gregory B, Kirchem A, Phipps S, et al. Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor alpha-chain expression by cytokines: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor alpha expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor alpha expression. J Immunol. 2003;170(11):5359-5366. doi: 10.4049/jimmunol.170.11.5359 [DOI] [PubMed] [Google Scholar]
  • 20.Owen DL, Farrar MA. STAT5 and CD4+ T cell immunity. F1000Res. 2017;6:32. doi: 10.12688/f1000research.9838.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Liao W, Schones DE, Oh J, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol. 2008;9(11):1288-1296. doi: 10.1038/ni.1656 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Lee J, Seong S, Kim JH, et al. STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis. Sci Rep. 2016;6:30977. doi: 10.1038/srep30977 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Ma CA, Xi L, Cauff B, et al. Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood. 2017;129(5):650-653. doi: 10.1182/blood-2016-09-737817 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Stella S, Massimino M, Manzella L, et al. Molecular pathogenesis and treatment perspectives for hypereosinophilia and hypereosinophilic syndromes. Int J Mol Sci. 2021;22(2):486. doi: 10.3390/ijms22020486 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Kontro M, Kuusanmäki H, Eldfors S, et al. Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia. Leukemia. 2014;28(8):1738-1742. doi: 10.1038/leu.2014.89 [DOI] [PubMed] [Google Scholar]
  • 26.Nicolae A, Xi L, Pittaluga S, et al. Frequent STAT5B mutations in γδ hepatosplenic T-cell lymphomas. Leukemia. 2014;28(11):2244-2248. doi: 10.1038/leu.2014.200 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Rajala HL, Eldfors S, Kuusanmäki H, et al. Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood. 2013;121(22):4541-4550. doi: 10.1182/blood-2012-12-474577 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Ding F, Wu C, Li Y, et al. A case of hypereosinophilic syndrome with STAT5b N642H mutation. Oxf Med Case Reports. 2021;2021(1):omaa129. doi: 10.1093/omcr/omaa129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol. 2012;130(3):607-612.e9. doi: 10.1016/j.jaci.2012.02.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Nagata Y, Todokoro K. Interleukin 3 activates not only JAK2 and STAT5, but also Tyk2, STAT1, and STAT3. Biochem Biophys Res Commun. 1996;221(3):785-789. doi: 10.1006/bbrc.1996.0674 [DOI] [PubMed] [Google Scholar]
  • 31.Rolling C, Treton D, Pellegrini S, Galanaud P, Richard Y. IL4 and IL13 receptors share the gamma c chain and activate STAT6, STAT3 and STAT5 proteins in normal human B cells. FEBS Lett. 1996;393(1):53-56. doi: 10.1016/0014-5793(96)00835-6 [DOI] [PubMed] [Google Scholar]
  • 32.Del Bel KL, Ragotte RJ, Saferali A, et al. JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. J Allergy Clin Immunol. 2017;139(6):2016-2020.e5. doi: 10.1016/j.jaci.2016.12.957 [DOI] [PubMed] [Google Scholar]
  • 33.Wang IM, Lin H, Goldman SJ, Kobayashi M. STAT-1 is activated by IL-4 and IL-13 in multiple cell types. Mol Immunol. 2004;41(9):873-884. doi: 10.1016/j.molimm.2004.04.027 [DOI] [PubMed] [Google Scholar]
  • 34.Ochiai K, Otaka K, Ito M, Tomioka H. The role of STAT1 in activation of IL-3- and IL-5-induced eosinophils by interferon gamma. Int Arch Allergy Immunol. 2001;124(1-3):237-241. doi: 10.1159/000053722 [DOI] [PubMed] [Google Scholar]
  • 35.Maier E, Duschl A, Horejs-Hoeck J. STAT6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol. 2012;42(11):2827-2833. doi: 10.1002/eji.201242433 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Yeh JE, Toniolo PA, Frank DA. JAK2-STAT5 signaling: a novel mechanism of resistance to targeted PI3K/mTOR inhibition. JAKSTAT. 2013;2(4):e24635. doi: 10.4161/jkst.24635 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Su Q, Wang F, Dong Z, Chen M, Cao R. IFN-γ induces apoptosis in human melanocytes by activating the JAK1/STAT1 signaling pathway. Mol Med Rep. 2020;22(4):3111-3116. doi: 10.3892/mmr.2020.11403 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Luschnig P, Kienzl M, Roula D, et al. The JAK1/2 inhibitor baricitinib suppresses eosinophil effector function and restricts allergen-induced airway eosinophilia. Biochem Pharmacol. 2021;192:114690. doi: 10.1016/j.bcp.2021.114690 [DOI] [PubMed] [Google Scholar]
  • 39.McInnes IB, Byers NL, Higgs RE, et al. Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations. Arthritis Res Ther. 2019;21(1):183. doi: 10.1186/s13075-019-1964-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Sehgal R, Ernste FC, Eckloff S. Successful treatment with baricitinib in a patient with refractory eosinophilic fasciitis. J Rheumatol. 2021;48(6):948-949. doi: 10.3899/jrheum.200998 [DOI] [PubMed] [Google Scholar]
  • 41.Šteňová E, Tarabčáková L, Babál P, Kašperová S. Hypereosinophilic syndrome—a rare adverse event of anti-cytokine treatment in rheumatoid arthritis resolved after Janus kinase inhibitor therapy. Clin Rheumatol. 2020;39(11):3507-3510. doi: 10.1007/s10067-020-05134-z [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Primers Used in Analysis of Archival Samples

eTable 2. Primers Used in Analysis of Index Patient Samples

Click here for additional data file. (252.1KB, pdf)
Supplement 2.

Data Sharing Statement

Click here for additional data file. (15.9KB, pdf)

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