New Data on Eosinophilic Cellulitis: Type 2 Inflammation and Targeting JAK1/JAK2 Pathways

Article

These new findings suggest the need for expansion of JAK1/JAK2 targeting approaches for treatment of eosinophilic cellulitis and other types of eosinophilic disease.

Eosinophilic cellulitis (EC) exhibits prominent type 2 inflammation which is characterized by the activation of JAK1/JAK2-STAT5 pathways, according to recent findings, indicating the potential for targeted treatments directed at JAK1/JAK2.1

These findings were the result of research conducted to expand current data and look into the characteristics of EC inflammation, as well as to examine pathways of cellular signal transduction which become activated with EC.

This new research was authored by Axel P. Villani, MD, PhD, from the Centre International de Recherche en Infectiologie at the Université de Lyon in France. The study’s investigators noted that prior to this study, EC’s pathogenesis has had relatively little exploration.2

“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,” Villani and colleagues wrote.

Background and Findings

The investigators’ research, conducted to expand their understanding of the inflammatory processes in EC and the signaling pathways involved, was conducted in France, from January of 2018 to December of 2021.

The research team utilized histology, JAK-STAT immunohistochemistry, and gene profiling on archival skin biopsy samples from EC patients and healthy controls, with data analysis being done between January of 2020 and January of 2022.

Skin lesion samples from study participants with EC and healthy controls were gathered by the investigators, and a diagnosis of EC was then established based on both clinical and histologic criteria, excluding other conditions.

A refractory EC participant was given baricitinib treatment, and disease severity was then assessed using Dermatology Life Quality Index and body surface area measurements. Gene expression analysis, RNA extraction, immunohistochemistry, and histologic staining were performed to investigate molecular mechanisms and signaling pathways in the lesions of EC patients.

With regard to their main outcomes, the team evaluated pruritus, lesional skin area, and inflammatory biomarkers in a single refractory EC patient who had been treated with oral JAK1/JAK2 inhibitor baricitinib (4 mg/d).

The investigators recruited 14 total patients with EC (7 women and 7 men) and used 8 healthy controls (4 women and 4 men) with a mean age of 52 years. The research team observed significant type 2 inflammation, which was characterized by elevated levels of chemokines CCL17, CCL18, and CCL26, as well as interleukin 13, along with the predominant activation of JAK1/JAK2-STAT5 pathways in EC lesions.

Notably, the team added that for the index patient with refractory EC, a remarkable clinical remission of skin lesions was shown to have been achieved following a single-month treatment with baricitinib.

“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,” they wrote.

The investigators noted that further investigation may be warranted to explore the engagement of the STAT6 pathway in EC, given its major role in the development of type 2 cytokine-producing cells, in addition to the observed activation of pSTAT5 and pSTAT1.

References

  1. Morot J, Del Duca E, Chastagner M, et al. Hyperactivation of the JAK2/STAT5 Signaling Pathway and Evaluation of Baricitinib Treatment Among Patients With Eosinophilic Cellulitis. JAMA Dermatol. Published online June 21, 2023. doi:10.1001/jamadermatol.2023.1651.
  2. 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.
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