Mycosis Fungoides-Like Atopic Dermatitis Represents a Th22-Dominant Inflammatory Endotype

Area of Science:

• Dermatology
• Immunology
• Genomics

Background:

• Early-stage mycosis fungoides (MF) diagnosis is challenging due to overlap with atopic dermatitis (AD).
• A subset of severe AD patients met MF criteria but were indistinguishable from AD and unresponsive to therapies, termed mycosis fungoides-like AD (mfAD).
• The study aimed to differentiate between malignant transformation and a distinct inflammatory endotype in mfAD.

Purpose of the Study:

• To investigate the underlying mechanisms of mycosis fungoides-like AD (mfAD).
• To determine if mfAD represents malignant transformation or a specific inflammatory endotype of atopic dermatitis (AD).
• To identify potential therapeutic targets for mfAD.

Main Methods:

• Single-cell RNA sequencing and T-cell receptor sequencing on skin biopsies from AD and mfAD patients.
• Integration and comparative analysis of publicly available MF and AD datasets.
• Spatial transcriptomic profiling to contextualize single-cell data within tissue architecture.

Main Results:

• T cells in mfAD were similar to AD and showed no genomic instability, ruling out malignancy.
• mfAD exhibited an oligoclonal Th22 cell expansion, not a single malignant clone.
• All mfAD patients responded rapidly to selective JAK1 inhibition, characteristic of inflammatory dermatoses.

Conclusions:

• mfAD is identified as a Th22-driven inflammatory endotype of AD, not a malignancy.
• This reclassification explains pseudo-monoclonality in MF misdiagnosis and dupilumab treatment failure.
• JAK inhibitors are proposed as a precision medicine strategy for mfAD.