2024-01-17 14:26:37
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Article information
- Author, Jasmin Fox-Skelly
- Role, BBC Future
-
12 minutes ago
Shayanne Boulet was 18 years old. At the end of her first year of college, out of the blue, she started having a painful itch.
“At first I thought it might be eczema,” she recalls. “But it was much more debilitating.”
“I couldn’t take a hot shower, I couldn’t concentrate on my homework, I couldn’t sleep because I was itchy for almost two hours in bed. I had to get up to clean myself because there was blood on the sheets.”
Boulet was diagnosed with prurigo nodular (PN), a chronic inflammatory skin disease.
The condition is one of many causes of chronic itch, defined by doctors as itching that lasts more than six weeks, and which, according to the National Institutes of Health, affects one in five people at some point in life.
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One in five people suffer from chronic itching, lasting weeks or months. But new treatments are being developed.
Chronic itching is associated with dermatological disorders such as eczema, hives and psoriasis, but also with other medical problems, including chronic kidney disease, kidney failure and lymphoma. In some cases, chronic itching can last for years and the sensation can be exasperating.
In the book The Divine Comedy, by Dante Alighieri (1265-1321), sinners condemned to the eighth circle of hell – the fraudsters – suffered “from the burning fury of the fierce itch that nothing can soothe.”
Many people with psoriasis can relate to Dante’s description of hell. The itching resulting from this condition has been compared to a fire ant attack.
Patients with liver disease have even undergone transplants because they were unable to deal with the itching sensation. And some cancer patients stop taking medications that could save their lives because they can’t stand the itching the medications cause.
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Chronic itching is very different from that caused by mosquito bites.
“Studies have shown that chronic itch is as debilitating as chronic pain, but in fact I think it’s even worse,” says physician and neuroimmunologist Brian Kim of the Icahn School of Medicine at Mount Sinai (New York). York, United States).
“With chronic pain, you feel a dull sensation of pain – a level 6 out of 10 kind of pain that just doesn’t go away,” he explains. “But you can sleep.”
“Chronic itching is different because it doesn’t give you any rest. People scratch it all night. From that perspective, it can be significantly more debilitating.”
Until recently, scientists didn’t really understand the causes of chronic itch, even though its incidence is high. The causes of acute itching are relatively well known.
If you are bitten by a mosquito or brush against poison ivy, immune cells in your skin release histamine and other substances that bind to small receptors on the surface of sensory nerves.
These substances activate receptors that send an itch signal to the spinal cord and brain.
Acute itching is irritating but can be treated with antihistamines or topical steroids. But antihistamines have no effect on chronic itching.
The result is that there has been little progress in treating itch over the past 360 years, since itch was first medically defined.
One reason is that scientists thought itching was just a mild form of pain.
This misconception can be highlighted in a study from the early 1920s.
Austrian-German physiologist Max von Frey (1852-1932) pricked the skin of laboratory study participants with sharp objects called spikes. He concluded that the initial sensation of pain was followed by a subsequent sensation of itching.
But in 2007, scientists led by Zhou-Feng Shen of the Washington University School of Medicine in St. Louis identified a receptor dedicated to itch on a subset of neurons (nerve cells) in the spinal cord.
Their study concluded that mice lacking this receptor were unable to feel itching. No matter how much you tickled or irritated them, they wouldn’t scratch. But the animals felt pain normally.
In other words, scientists have discovered a set of neurons in the spinal cord that specifically transmit the itch sensation to the brain.
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Image caption,
Scientists have discovered neurons in the spinal cord that specialize in transmitting the sensation of itching to the brain.
Since then, scientists have discovered other neurons and receptors specific to itch.
Mrgprs-like receptors have been found in sensory neurons present in the skin. They project directly to the brain and appear to play a key role in transmitting itch.
In 2017, Brian Kim and colleagues at the University of Washington’s Center for the Study of Itch and Sensory Disorders discovered that skin inflammation could cause immune cells to release chemical messengers called IL-4 and IL-3. . These substances, called cytokines, also bind to sensory neurons in the skin, causing itching.
“An interesting point about Brian Kim’s work is that he discovered that these molecules not only bind to itch neurons, but also reduce the threshold for other molecules in the skin to activate these neurons. By Therefore, they often sensitize allergy sufferers so that they feel more itchy,” explains dermatology professor Marlys Fassett, from the University of California, San Francisco, USA.
Fassett focused his studies on another “itch cytokine” called IL-31. This cytokine has previously been shown to activate itch-specific neurons.
Fassett says work will soon be published demonstrating that, like other itch cytokines, IL-31 also reduces the threshold of itch neurons, making them more common and easier to manifest.
In a 2023 study, Fassett found that in addition to causing itching, IL-31 also reduces nearby inflammation. As a result, the itching sensation, at any given moment, diminishes.
His team removed a gene encoding IL-31 in mice and exposed the animals to dust mites, a common itch allergen.
As expected, the mites did not cause itching in mice lacking IL-31. But inflammation in the area skyrocketed.
“It has been known for 15 years that if you inject IL-31 into the skin or spinal fluid of a mouse, the animal immediately begins to scratch uncontrollably,” according to Fassett.
“But the dilemma remained: If you removed this itch cytokine, the inflammation, instead of going down into the tissues, increased. And that didn’t make much sense, since in most tissues where there is itch and inflammation together, you should expect them to move together.”
Apparently, skin neurons activated by IL-31 also suppress the immune response, thereby keeping inflammation under control.
This discovery is important. This means that anti-itch medications that target IL-31 can have unintended consequences, causing uncontrollable inflammation.
Treatment of itching
Anti-itch medications are already in development.
Nemolizumab, for example, targets the IL-31 receptor. It has already completed phase 2 and 3 clinical trials for the treatment of atopic dermatitis – a form of eczema that causes dry, itchy skin and inflammation.
For people suffering from this debilitating disease, there is now dupilumab, a recently approved drug that inhibits IL-4 and IL-13 receptors. And other drugs, such as EP262, abrocitinib and upadacitinib, are also in phase 3 trials for the treatment of atopic dermatitis.
EP262 blocks Mas-related G protein-coupled receptor X2 (MRGPRX2), while abrocitinib and upadacitinib interfere with IL-4 and IL-13 processes by inhibiting a receptor called JAK1.
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Image caption,
Chronic itching is linked to dermatological disorders such as eczema, hives and psoriasis, among others.
Chronic itching is linked to dermatological disorders such as eczema, hives and psoriasis, among others.
Other itch-related conditions could also benefit from new treatments.
In 2023, for example, doctor and professor of dermatology Gil Yosipovitch, of the Miller University School of Medicine, in Miami (United States), worked with Brian Kim and other researchers to carry out phase 3 trials on the The use of dupilumab in the treatment of prurigo nodularis (PN) – the same condition as Shayanne Boulet.
After 24 weeks, 60% of participants who received dupilumab saw a significant reduction in itching, compared to 18.4% of participants who received a placebo.
Therefore, the US Food and Drug Administration (FDA) approved the use of dupilumab for the treatment of patients with PN.
“NP is one of the conditions that dermatologists say causes the most itching, and until recently there was no effective treatment,” says Yosipovitch. “Because of this, patients suffered a lot.”
“It’s an exciting time for our patients. They feel like there’s finally hope. I’ve had so many previously frustrated and unhappy patients come to me and say ‘the medications have save the life”.
Meanwhile, Brian Kim’s new lab at the Icahn School of Medicine is testing diphelykephalin for the treatment of notalgia paresthetica, a nerve disorder characterized by persistent itching in the upper back.
The FDA has approved the use of diphelycephalin for the treatment of moderate to severe itch associated with chronic kidney disease in adults receiving hemodialysis. But, in phase 2 testing, it was also found to be moderately effective in treating notalgia paresthetica.
Together, these drugs provide hope that, until recently, did not exist.
“I feel like I’m myself again and can continue to live as best I can,” Boulet says. She participated in Yosipovitch’s study.
“Sometimes I scratch a little, but only for 10 minutes,” she says. “My quality of life is much better than before.”
Dupilumab is not suitable for all patients, but other drugs are on the way.
“I think in the next five years we will be able to control the majority of these patients,” Yosipovitch says.
“This is a very rewarding time for doctors like me who have been caring for the suffering of these patients for so many years.”
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