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- Author, Jasmin Fox-Skelly
- Role, BBC Future
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January 17, 2024
Shayanne Boulet was 18 years old. At the end of her freshman year, she developed a painful itch out of the blue.
“At first I thought it might be eczema,” she remembers. “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 in bed for almost two hours. I had to get up to wash 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 itching, which doctors define as itching that lasts longer than six weeks and which affects one in five people at some point in their life, according to the National Institutes of Health.
Also read on BBC Africa:
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One in five people suffer from chronic itching that lasts weeks or months. However, new treatment methods are being developed.
Chronic itching is associated with dermatological conditions 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 feeling can be unbearable.
In the book “The Divine Comedy” by Dante Alighieri (1265-1321), sinners condemned to the eighth circle of hell – the impostors – “suffered from the burning fury of the violent itch which nothing can relieve.”
Many people with psoriasis can relate to Dante’s description of hell. The resulting itching has been compared to a fire ant infestation.
Patients with liver disease have even had transplants because they couldn’t cope with the itching. And some cancer patients stop taking life-saving medications because they can’t stand the itching the drugs cause.
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Chronic itching is very different from that caused by mosquito bites.
“Studies have shown that chronic itching is as debilitating as chronic pain, but 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 type of pain that just won’t go away,” he explains. “But you can sleep.”
“Chronic itching is different because it doesn’t give you peace of mind. People scratch him all night long. From that perspective, it can be much more debilitating.”
Until recently, scientists didn’t really understand the causes of chronic itching, even though it’s common. The causes of acute itching are relatively well known.
When you are bitten by a mosquito or encounter 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. However, antihistamines have no effect on chronic itching.
The result is that there has been little progress in the treatment of itch in the last 360 years, since it was first defined medically.
One reason for this is that scientists thought itching was just a mild form of pain.
This misunderstanding can be illustrated in a study from the early 1920s.
The Austro-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 Washington University School of Medicine in St. Louis identified an itch receptor on a subset of neurons (nerve cells) in the spinal cord.
Their study concluded that mice lacking this receptor were unable to experience itching. No matter how much you tickled or teased them, they wouldn’t scratch. But the animals felt pain normally.
In other words: Scientists have discovered a series of neurons in the spinal cord that specifically transmit the sensation of itching to the brain.
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Scientists have discovered neurons in the spinal cord that are specialized in transmitting the feeling of itching to the brain.
Since then, scientists have discovered additional neurons and receptors specific to itch.
Mrgprs-like receptors have been found in sensory neurons in the skin. They project directly into the brain and appear to play a key role in the transmission of 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 can 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 and cause itching.
“An interesting point about Brian Kim’s work is that he discovered that these molecules not only bind to itchy neurons, but also reduce the threshold for other molecules in the skin to activate these neurons. Therefore, they often sensitize allergy sufferers, so that they feel increased itching,” explains dermatology professor Marlys Fassett from the University of California in 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 showing that IL-31, like other itch cytokines, also lowers the threshold of itch neurons, causing them to occur more frequently and manifest more easily.
In a 2023 study, Fassett found that IL-31 not only causes itching but also reduces adjacent inflammation. This means that the feeling of itching subsides at any time.
His team removed a gene encoding IL-31 from mice and exposed the animals to house dust mites, a common itch allergen.
As expected, the mites did not cause itching in mice lacking IL-31. But the 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 starts scratching uncontrollably,” said Fassett.
“But the dilemma remained: if you removed this itch cytokine, the inflammation increased instead of penetrating the tissue. And that didn’t make much sense because in most tissues where itching and inflammation occur at the same time, you have to expect that they’re supposed to contract.”
Apparently, skin neurons activated by IL-31 also suppress the immune response and thus keep inflammation under control.
This discovery is important. This means that anti-itch medications that target IL-31 can have unintended consequences and cause uncontrollable inflammation.
Treatment of itching
Anti-itch medications are already in development.
Nemolizumab, for example, targets the IL-31 receptor. The company 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 the 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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Chronic itching is associated with dermatological diseases such as eczema, hives and psoriasis, among others.
Chronic itching is associated with dermatological diseases such as eczema, hives and psoriasis, among others.
Other itch-related diseases could also benefit from new treatments.
For example, in 2023, doctor and professor of dermatology Gil Yosipovitch from Miller University School of Medicine in Miami (USA) collaborated with Brian Kim and other researchers to conduct phase 3 studies on 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 experienced a significant reduction in itching, compared to 18.4% of participants who received a placebo.
Therefore, the US Food and Drug Administration (FDA) has 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. “As a result, the patients suffered a lot.”
“It is an exciting time for our patients. You feel like there is finally hope. I have had so many previously frustrated and unhappy patients come to me and say, ‘The medication saved their lives’.”
Meanwhile, Brian Kim’s new lab at the Icahn School of Medicine is testing diphelykephalin as a treatment for notalgia paresthetica, a nerve disorder characterized by persistent itching in the upper back.
The FDA has approved the use of diphelycephalin to treat moderate to severe pruritus associated with chronic kidney disease in adults receiving hemodialysis. However, it was also found to be moderately effective in treating notalgia paresthetica in phase 2 testing.
Taken together, these drugs offer hope that didn’t exist until recently.
“I feel like I can be myself again and continue living as best as I can,” says Boulet. She took part 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,” says Yosipovitch.
“This is a very rewarding time for doctors like me who have cared about the suffering of these patients for so many years.”
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