Episode 22 - TYK2 inhibition improves the hallmarks of cutaneous lupus subtypes

In this episode of BJD Talks, Sam and Meera discuss the article ‘Tyrosine kinase 2 inhibition improves clinical and molecular hallmarks in subtypes of cutaneous lupus’ by Wasserer et al. The full article can be accessed at https://doi.org/10.1093/bjd/ljaf293 

*This podcast was generated by an AI tool created by 67Bricks for the British Association of Dermatologists* 

Transcript

SPEAKER_01 0:00

Welcome to BJD Talks, the official podcast of the BJD. I'm Sam.

SPEAKER_00 0:04

And I'm Mira. In this episode, we will be discussing the article by Sophia Wasserer et al. Tyrosine kinase 2. Inhibition improves clinical and molecular hallmarks in subtypes of cutaneous lupus, published in August 2025 and included in the December 2025 issue.

SPEAKER_01 0:24

Cutaneous lupus erythematosis, or CLE, is a challenging autoimmune skin condition characterised by significant inflammation, largely driven by type 1 interferons and T cell-mediated autoimmunity. Mira, there are three main subtypes: acute, subacute, and chronic discoid, each presenting unique clinical difficulties.

SPEAKER_00 0:45

Indeed, Sam. What's particularly intriguing is the role of tyrosane kinase 2, or TIC2, an intracellular signalling protein. It transmits signals from type 1 interferons, such as interferinal, which drive inflammation in CLE, as well as from cytokines like IL12 and IL23. For this reason, the study explores how ducrovacitinib, a TIC-2 inhibitor, acts on these molecular pathways in lupus models and also demonstrates therapeutic potential for CLE patients who are resistant to conventional treatments.

SPEAKER_01 1:22

The researchers used RNA sequencing and immunohistochemistry to analyse skin biopsies from CLE patients, as well as a three-dimensional skin model to recreate inflammatory settings. They then stimulated primary human keratinocytes with interferons and cytokines from lupus patients to mimic cutaneous lupus inflammation before applying ducrovacitinib. Fascinating approach.

SPEAKER_00 1:46

Very much so. They observed elevated tic2 expression in CLE lesions, far higher than in other inflammatory skin conditions or healthy skin. Crucially, inhibiting TIC2 reduced key inflammatory signals like CXCl9 and CXCL10, whilst also restoring skin architecture. The reconstructed epidermis even showed reversal of inflammation-induced damage.

SPEAKER_01 2:10

There were also four case studies involving therapy-resistant CLE, spanning subacute, discoid, acute, and chillblane lupus. Remarkably, oral ducravacitinib led to visible improvements within weeks. One notable finding was the rapid symptom relief, with improvements in physician global assessment scores and quality of life metrics by week four.

SPEAKER_00 2:32

Precisely. The rapidity is striking compared to existing treatments like hydroxychloroquine, which often require extended periods before even partial improvement. The manifold action of TIC2 inhibition, addressing interferon signalling, and T cell inflammation seems to drive this efficiency.

SPEAKER_01 2:51

The study also links ducrovacetinib's effects to other inflammatory conditions like psoriasis, for which it already has FDA and EMA approval. Its safety and efficacy across different diseases add weight to its potential for CLE. How do you view this development within the broader context of CLE treatment?

SPEAKER_00 3:10

This study provides both clinical and mechanistic evidence supporting targeted therapies for CLE. If larger trials confirm these findings, TIC-2 inhibitors could become integral to treatment, particularly for patients unresponsive to current options. They also hold promise in combination with existing therapies.

SPEAKER_01 3:29

That said, limitations remain, notably the small sample size and the off-label application of ducrovacetinib. We'll need robust phase 2 and 3 data to address long-term safety and efficacy.

SPEAKER_00 3:42

Agreed. Still, these results are highly encouraging. CLE has long been a complex condition to manage, making this a potentially significant advancement. In summary, TIC2 inhibition reduces inflammation, restores epidermal integrity, and delivers rapid clinical improvement.