People with Sweet's syndrome often wake up with a fever, body aches, and blisters on their neck, limbs and face. Also known as acute febrile neutrophilic dermatosis, it is an inflammatory skin disease marked by those severe symptoms and elevated counts of white blood cells.
Sweet's syndrome can be triggered by general upper-respiratory infections, certain medications, pregnancy, and even some cancers. Aside from taking steroids (often over prolonged periods), addressing any underlying cause, and waiting for the inflammation to subside, no medication exists to stop the disease, and many patients face chronic Sweet's syndrome and flare ups. And while the disease only strikes roughly two in a million people every year in the United States, the most severe cases are persistent and can require multiple hospitalizations.
Now, building on their previous research, a team of dermatologists and researchers at the Perelman School of Medicine at the University of Pennsylvania has found a way to directly target neutrophils, a type of immune cell implicated in the disease. The researchers say that a first-of-its-kind targeted treatment for Sweet's syndrome may be possible by adopting their method of moderating rogue neutrophils. This would happen by zeroing in on protein receptors called SAA1 and FPR2. The new study was published in the Journal of Clinical Investigation.
The science behind Sweet's syndrome
Neutrophils are the most common type of white blood cell and travel to areas of infection to destroy invaders that threaten the body.
"In earlier work, we showed that certain genetic mutations can make more neutrophils move into the skin," said study author Thomas Leung, MD, PhD, an associate professor of Dermatology at Penn. "But until now, it wasn't clear why neutrophils, which are typically short-lived, stay there so long or how they contribute to ongoing inflammation."
This new study used skin cells and blood from individuals with Sweet's syndrome. Leung and his colleagues found that, in people with the disease, many neutrophils turn into long-lived versions that act improperly, recruiting and activating other immune cell types including T cells. They also found that these rogue neutrophils irritate skin cells called keratinocytes and release a protein called SAA1. This protein prolongs the life of the neutrophils, keeping them in this alternative activation state and leading to even more SAA1 secreted by the skin cells.
"The neutrophils, keratinocytes, and SAA1 get trapped in this cycle where they are all triggering each other, worsening inflammation, and an increasing severity of symptoms," said Misha Rosenbach, MD, study author and the Paul R. Gross Professor of Dermatology at Penn.
The most substantial finding came from in vitro experiments where researchers used antibodies to specifically inactivate the two signaling molecules SAA1 and FPR2. Essentially, turning off SAA1/FPR2 signaling caused most neutrophils to die naturally and fall out of the harmful activation state. From there, the cycle of inflammation stopped.
Looking to the future
"Current treatment of Sweet's syndrome typically requires corticosteroids which, among having unavoidable long-term side effects like diabetes and osteoporosis, also make people more likely to develop and less likely to fight off infections," said Rosenbach.
"Using steroids to treat Sweet's syndrome is like swinging a big hammer at a problem," said Leung. "It's powerful and effective but blunt. Developing medications that turn off SAA1 and FPR2 receptors could replace the need for steroids for these individuals and actually be more effective.
There are some medications in clinical trials that were designed to treat amyloidosis that may target SAA1 receptors, but there is nothing currently FDA-approved that can be used off-label. Additionally, the Penn researchers found the greatest impact on neutrophils came when targeting both SAA1 and FPR2 receptors, so an ideal drug candidate for Sweet's syndrome would do both.
"Our research reflects this era of medicine where, due to discoveries about how diseases actually develop, treatment approaches are becoming more precise and specific," said Rosenbach. "The most important thing now is keeping up the momentum."
