Researchers from around the globe, based at the Max Planck Institute of Biochemistry, have made a significant breakthrough that could save lives for patients suffering from toxic epidermal necrolysis, a rare but often deadly reaction to commonly prescribed medications that leads to severe skin detachment. By employing cutting-edge spatial proteomics, one of the most advanced techniques in molecular biology, they discovered that the inflammatory JAK/STAT pathway is the primary factor driving this disease. After validating their results with pre-clinical models, they treated the first seven patients in the world with JAK inhibitors, all of whom experienced quick and complete recoveries.
To investigate toxic epidermal necrolysis, researchers utilized spatial proteomics to examine skin samples from affected patients. This innovative method, dubbed Deep Visual Proteomics, combines high-powered microscopy with artificial intelligence for analysis, laser-guided microdissection, and ultra-sensitive mass spectrometry. This technique allowed them to focus on individual cells, creating a detailed map of the numerous proteins involved in this lethal reaction.
Thierry Nordmann, the lead author and a clinician-scientist at the Max Planck Institute of Biochemistry as well as a senior dermatologist at Ludwig Maximilians Universität München, commented: “By applying spatial proteomics to legacy patient samples affected by toxic epidermal necrolysis, we could accurately isolate and study specific cell types, gaining insights into the changes occurring in these patients’ skin. We discovered a pronounced hyperactivation of the inflammatory JAK/STAT pathway, which suggests a potential for intervention using JAK inhibitors—drugs already utilized for treating other inflammatory ailments like atopic dermatitis and rheumatoid arthritis.”
Toxic epidermal necrolysis is an infrequent but critically dangerous reaction to widely used medications, including allopurinol (for gout management) and certain antibiotics. It results in extensive blistering and skin loss. The condition has a mortality rate of up to 30 percent and can escalate rapidly from a seemingly mild rash to a life-threatening situation. Previously, no effective therapies were available, with treatment primarily focusing on supportive care.
The research team confirmed their findings through a series of preclinical studies, using in vitro models as well as two distinct mouse models. The findings were consistently encouraging: JAK inhibitors demonstrate significant potential in treating this dire condition. Their discoveries were further bolstered by an international collaboration involving six countries, underscoring the importance of teamwork in addressing pressing medical issues.
A new treatment option for patients?
Working in conjunction with clinical teams led by Chao Ji at the First Affiliated Hospital of Fujian Medical University in China, the researchers treated patients with toxic epidermal necrolysis using JAK inhibitors. Remarkably, all seven patients showed swift improvement and complete recovery after treatment.
Lars French, co-author and chair of Dermatology at LMU Munich, stated: “The new evidence suggesting that inhibiting the JAK/STAT pathway could reduce the high mortality associated with this serious adverse drug reaction opens the door for clinical trials aimed at securing regulatory approval for JAK inhibitors—addressing one of the most urgent unmet needs in healthcare.”
While larger clinical trials are still necessary to verify the effectiveness and safety of JAK inhibitors for toxic epidermal necrolysis, this research offers new hope for affected patients. Additionally, it presents fresh opportunities for repurposing existing drugs and developing new treatments. The Max Planck Society, in collaboration with Ludwig Maximilian University, has applied for patents regarding the use of JAK inhibitors in managing toxic epidermal necrolysis and related conditions, paving the way for further advancements.
Matthias Mann remarked, “Our findings not only create new possibilities for addressing this reaction but also showcase the potential of spatial proteomics in facilitating medical advancements. To the best of our knowledge, this marks the first instance where spatial omics technology has resulted in a direct, positive impact in a clinical setting by uncovering a treatment that has already altered lives for the better. This methodology could be extended to a variety of diseases, possibly speeding up drug development across multiple medical disciplines.”
