Study could lead to cure for rare fatal skin disease

Researchers claim to have cured patients with a rare but fatal skin disease — toxic epidermal necrolysis (TEN) — using an existing class of drugs.

TEN — a fatal condition that currently has limited treatment options and no approved cure — is triggered by an extremely severe adverse reaction to common medications, such as allopurinol (used to treat gout) and certain over-the-counter antibiotics. With a mortality rate of around 30%, the disease can rapidly progress from a seemingly harmless rash into a life-threatening condition.

A study involving WEHI has now identified a new driver of the disease that can be therapeutically targeted with an existing class of drugs. The researchers used JAK inhibitors — a class of drugs currently approved for the treatment of inflammatory diseases like rheumatoid arthritis — to treat patients with the disease, said second author and WEHI molecular biologist Dr Holly Anderton.

“All seven people treated with this therapy in our study experienced rapid improvement and a full recovery, in staggering results that has likely unlocked a cure for the condition,” Anderton said.

By the time patients present to hospital with TEN, their symptoms are already at a critical stage, requiring similar treatment to burns victims, including intensive care and life support. “It can take a patient weeks to recover from the damage, even after they’ve stopped taking the medication that triggered the adverse reaction,” Anderton said.

“Being able to rapidly halt progression of this disease, as we have seen in our study, will make a huge difference to the standard of care for patients diagnosed with this life-threatening condition.”

The researchers, in collaboration with the Max Planck Institute of Biochemistry in Germany, used spatial proteomics to analyse skin samples from patients with TEN. This allowed the team to zoom in on individual cells and study them in detail, creating a map of the thousands of proteins that drive the disease.

Dr Thierry Nordmann, first author and clinician scientist at the Max Planck Institute, said, “By applying spatial proteomics to archived patient samples suffering from toxic epidermal necrolysis, we were able to precisely isolate and analyse individual cell types and understand what is actually 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”, Nordmann said. This theory was tested across multiple preclinical studies, including in a unique disease-approximating mouse model developed by Anderton and colleagues at WEHI.

The overwhelmingly positive results from these studies allowed researchers to proceed directly to trialling the treatment in TEN patients. This led to the result of seven patients in Germany being cured of the life-threatening disease.

The researchers hope their milestone findings will soon pave the way for a clinical trial aimed at the regulatory approval of JAK inhibitors as a cure for TEN.

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