Researchers have successfully treated seven patients experiencing toxic epidermal necrolysis (TEN) using JAK inhibitors. All seven patients showed rapid and full recovery from the severe reaction.
In a paper published online ahead of print in Nature (Oct. 16, 2024), investigators describe how they used spatial proteomics to analyze skin samples from patients with toxic epidermal necrolysis. This allowed them to systematically map molecular changes associated with TEN and identify potential targets for treatment.
Their method, known as deep visual proteomics, combines microscopy with AI-driven analysis, laser-guided microdissection and ultra-high sensitivity mass spectrometry.
The analysis revealed marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN and phosphorylated STAT1 activation. When the investigators tested targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro, the treatment reduced keratinocyte-directed cytotoxicity.
In a press release, Thierry Nordmann, first author, clinician-scientist at the Max Planck Institute of Biochemistry and senior dermatologist at the Ludwig Maximilians Universität München in Germany, explains: “By applying spatial proteomics to archived patient samples suffering from toxic epidermal necrolysis, we were able to precisely isolate and analyze individual cell types and understand what is occurring in the skin of these patients. We identified a striking hyperactivation of the inflammatory JAK/STAT pathway, revealing an opportunity to intervene in this deadly condition with JAK inhibitors, a class of drugs already used to treat other inflammatory conditions, such as atopic dermatitis or rheumatoid arthritis.”
The researchers validated their findings across a variety of preclinical studies, including in vitro models and two distinct mouse models. Their results were consistent and overwhelmingly positive: JAK inhibitors show real potential in treating TEN.
Then, in partnership with clinical teams led by Chao Ji at the First Affiliated Hospital of Fujian Medical University in China, the researchers administered JAK inhibitors to seven patients experiencing TEN. All seven patients experienced rapid improvement and full recovery upon treatment.
Lars French, co-corresponding author and Chair of Dermatology at LMU Munich, said in the release: “The new evidence that inhibition of the JAK/STAT pathway has potential to reduce the high mortality of this severe adverse cutaneous drug reaction paves the way for clinical trials aimed at regulatory approval of JAK inhibitors to solve one of the most serious unmet needs in medicine.”
“Our findings not only open new avenues for treating this reaction but also highlight the potential of spatial proteomics in driving medical breakthroughs,” said Dr. Matthias Mann, Director of the Max Planck Institute of Biochemistry. “To our knowledge, this is the first time a spatial omics technology has made an immediate and tangible impact in the clinic by identifying a treatment that has already changed people's lives for the good. This approach could be applied to a wide range of diseases, potentially accelerating drug discovery across multiple fields of medicine.”
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